Library of Organoid “Mini-Guts” Helps Identify New Pathways in IBD
Dr. Thomas Dennison describes how CRISPR screening of lab-grown mini-guts could lead to new treatments for IBD.

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Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that affects an estimated 2.4 to 3.1 million people in the US alone. Despite decades of research, identifying the underlying cause of IBD has remained elusive, in part due to the difficulty in modeling the disease.
Researchers at the University of Cambridge have grown mini-guts – known as organoids – to help understand IBD, showing that epigenetic controls that modify DNA in gut cells play an important role in how IBD presents in patients.
The research, published in the journal Gut, used cells donated from 168 patients with Crohn’s disease – a type of inflammatory bowel disease – to generate a biobank of over 300 intestinal epithelial organoids (IEOs). Using these organoids, the researchers showed that the epithelia in the guts of Crohn’s disease patients have different epigenetic patterns on their DNA. In addition, they found a correlation between these changes and the severity of the disease.
Technology Networks spoke with Dr. Thomas Dennison, a postdoctoral research associate working in the Milner Therapeutics Institute at the University of Cambridge, to learn more about the advantages of using patient-derived organoids for modeling IBD. Dennison also describes how CRISPR screening tools will be key to further unraveling the mechanisms behind IBD.
Could you elaborate on how these “mini-guts” have advanced our understanding of patient-specific variations in IBD?
Current treatments for IBD are limited. They don't cure the disease and patients require ongoing treatment. High rates of people don't respond to treatments or lose responsiveness over time, so it's difficult to predict who will respond to which treatments and whether patients will continue responding well. This is often attributed to the fact that most treatments target inflammation, a symptom of IBD, rather than the underlying cause of the disease.
To better understand the underlying cause of IBD we can use patient-derived organoids that better mimic aspects of the disease. These are designed to reflect the patient and are extracted from the inflammatory environment. This allows us to look at mechanisms that might underpin the disease, rather than signals coming from the inflammation itself.
Toward this goal, we generated a biobank of 312 IEO lines from IBD patients and controls to identify stable disease-associated molecular patterns. Using the biobank, we performed epigenetic profiling to identify differences between patients and controls. We discovered hypomethylation in genes associated with major histocompatibility complex (MHC) class 1 pathways.
Organoids are great in what they can describe but their functional assays are not as well developed as in 3D cell cultures. We are now working on developing these techniques for organoids, particularly CRISPR screening techniques, to further interrogate the mechanisms behind IBD.
Many steps and people are involved when developing a biobank and I’d say one of the biggest challenges is sourcing donor samples. What I find interesting is that although the pediatric department is smaller than the adult gastrointestinal department in terms of the number of patients getting endoscopies, we can collect more samples there. I think the reason is that the clinical team is relatively small, so they can buy into the project. We've got good links with the academic team and patients so we could collect large numbers of samples. I would say above 95% of people asked to give samples said yes to donating.
More and more people are working with organoids, but it generally tends to be with relatively small numbers of samples. IBD is such a variable condition that you need large sample numbers to get to the bottom of the mechanisms involved in the disease. Many papers will conclude that a certain mechanism is important for IBD, but if they’ve only tested the hypothesis on a small patient cohort it may only be important in a small subset of patients, and not scalable to the wider disease.
The field of functional genomics and CRISPR screening has been growing over the past few years. However, because the technology is relatively new and complicated, it's mostly been focused on several cancer cell lines while models for diseases have been steadily growing in complexity. You can get lots of impressive data from CRISPR screening, but if this is done on models that don’t accurately reflect the disease or the patient then it’s not necessarily going to help patients in the long run.
If we can develop methods that we can readily apply to better models that reflect the patient’s disease, then we will vastly increase the quality of data we generate and eventually identify better drug targets and improve attrition rates.
The next step of our research is to further build on the CRISPR methods we’re developing and increase their scalability. We're going to do a pilot screen, to prove the principle of the methods. Then we want to use these methods to better understand the epigenetic mechanisms involved in IBD to eventually screen for novel drug targets.