Revolutionising IBD Research: James Lee Discusses Landmark Findings
Interviewed by Isabella Haaf (EFCCA's Head of Communications)
In a groundbreaking discovery, UK researchers have identified a new biological pathway that drives Inflammatory Bowel Disease (IBD) and could potentially be targeted with existing drugs. This significant finding - published in the nature journal - was the result of collaborative research conducted by the Francis Crick Institute, University College London (UCL), and Imperial College London. The team uncovered a region of DNA that enhances the activity of specific macrophages (white blood cells), thereby driving inflammation and increasing the risk of IBD. Today, we have the privilege of speaking with James Lee, the lead researcher of this study, to gain deeper insights into this discovery and its potential implications for IBD treatment and management.
The European Federation of Crohn's and Colitis Associations, representing 46 national IBD patient associations, is thrilled to hear about your research findings. Could you explain in simple terms what your discovery is about?
We know from numerous genetic studies conducted over the last 10 to 15 years that both Crohn's disease and Ulcerative Colitis (collectively referred to as Inflammatory Bowel Disease) have a significant genetic component.
We have identified numerous regions in our DNA that contribute to the development of these diseases and know their locations. However, the challenge lies in understanding the specific mechanisms within these regions that lead to IBD. This knowledge is important because moving from identifying where the associations are to understanding what exactly goes wrong can potentially lead to new ways to treat the disease.
We began investigating a DNA region identified about 15 years ago that is known to increase the risk of both Crohn's disease and Ulcerative Colitis, as well as several other diseases. The function of this region remains unclear, partly because there are no obvious genes located at the site of the association.
You need to understand that in fact, only about two percent of our DNA is used for encoding genes; the rest was once considered "junk" because its function was unknown. When genetic associations are found in large stretches of DNA without any genes, they are often overlooked in favor of associations that are easier to understand.
We initially realised that since this region not only increased your risk of developing IBD but also increased your risk of getting various other diseases, it must hold significant importance. When a region elevates the risk of multiple diseases, it indicates a crucial role in human health. Moreover, it likely influences the immune system because these diseases are all characterized by an abnormal immune response.
What exactly did you discover in this region that helps us to better understand IBD?
We basically discovered that within this region, there is something called an enhancer. An enhancer functions like a volume dial for genes—it can “turn up” or “turn down” the amount of a nearby gene. We observed that this enhancer is specifically active in a type of cells known as macrophages. Macrophages are important in the context of IBD for two main reasons. Firstly, in IBD, there is a significant influx of macrophages into the intestine, where they contribute to inflammation. Secondly, some of the most effective treatments for IBD currently target the inflammatory chemicals produced by these macrophages.
We first managed to identify the gene that was targeted by this enhancer, but the exact function of this gene was unknown. Then, through a series of experiments where we could “switch off” or “switch on” the gene, we realised that what we had found was actually the central regulator of inflammation in macrophages, as switching it on made macrophages become very inflammatory, while switching it off made them lose inflammatory capabilities. Interestingly, even in resting macrophages that were not previously activated, ‘activating’ this gene caused them to look like the macrophages found in the inflamed guts of patients with Crohn's disease and Ulcerative Colitis. So, by just turning on one gene made macrophages look like those found in patients with IBD. This discovery marked the initial breakthrough in uncovering this entire pathway.
This is really exciting news because, if I understand correctly, targeting this pathway could mean that patients won't have to endure the frustration of trying multiple treatments before finding relief?
Yes, the second exciting discovery we made is figuring out a method to deactivate this pathway. Currently, some of the most effective drugs for IBD target individual molecules that macrophages produce, such as anti-TNF or anti-IL23. However, we've learned that targeting multiple molecules simultaneously can sometimes be more effective than targeting just one. For researchers the ultimate goal has been to identify a single protein that, if targeted, could effectively switch off all these pathways, which would potentially be much more effective for treatment.
We have found a way of “switching off ” this pathway using a drug already approved for use in people, though not yet for inflammatory diseases. However, this drug isn't yet ready for patient trials because it's not safe for long-term use, and of course, IBD is a chronic condition.
We are now working hard to make this drug more targeted and safer. We hope this effort will result in a much more effective IBD treatment in the near future. This could spare patients from the trial and error of current treatments, offering one drug capable of addressing multiple pathways and significantly improving patient outcomes.
When you mention the near future, could you provide a rough timeframe or specify how soon we might expect to see developments or changes based on your findings?
It's a crucial question, and I believe we have a couple of advantages. First, transitioning from basic discovery to a drug typically takes 10 to 15 years. However, we have a significant head start because the drugs we're considering have already undergone comprehensive safety testing in humans. This prior safety testing gives us a substantial advantage compared to starting from scratch.
And fortunately, we have already begun developing molecules designed to specifically target inflammatory macrophages. These molecules are currently undergoing testing in the lab, with development having started approximately six months ago.
If these molecules prove effective, the next step will be to develop a drug suitable for human use. I am optimistic that within the next two years, we will have a drug ready to undergo the necessary regulatory approvals for eventual use in patients. Following that, I hope to begin clinical trials shortly thereafter. Ideally, I envision dosing the first patient with a drug targeting this pathway within the next two to three years, initially through trials and eventually obtaining approval for broader use.
You previously talked about the genetic component related to your research. Does this have any implications for predicting the disease? As you can imagine, this is a major concern for individuals with a family history of IBD?
First and foremost, it's important to reassure people that discovering a strong genetic link does not mean everyone in the family will develop IBD. We have long understood that if someone has Crohn's disease or UC, the likelihood of any first-degree relatives—such as children, siblings, or parents—also developing IBD is only about 5-10% over their lifetime. There's no need for anyone to panic about this.
Another important aspect of IBD is that it typically requires multiple pathways to be dysregulated and then is triggered by environmental factors. This is why people don't usually develop IBD at birth but rather later in life, typically around 20-30 years of age. While this genetic pathway we've identified is significant, it alone isn't sufficient to predict who will develop IBD.
What this means is that both genetics and an environmental trigger are necessary. When I explain this to patients I often use this analogy—imagine a gun being fired – genetic risk factors are like the bullets that are loaded into the gun, and the environmental factor is what pulls the trigger. If a gun is loaded but the trigger is never pulled, it won't fire and you won’t develop the disease, similarly, if the trigger is pulled but the gun isn't loaded in the first place, it also won't fire.
We've received many questions through social media and other channels from individuals worried about their first-degree relatives but there is no need for concern. The main excitement about our work is that we've identified a central pathway involved in IBD that we believe can be targeted with drugs. This discovery doesn't have major implications for whether people's first-degree relatives or children will develop IBD in the future.
Talking about implications, it's correct to say that while this discovery is certainly going to be a game-changer for IBD, it doesn't have any direct impact on current treatment options at the moment?
That's correct. I've had many people contact me asking, "Can we join the clinical trial? Can I stop my medication now?" The answer is: if you're already on medication that's working for your IBD, you should continue with it.
When we're ready for clinical trials, we'll announce it, and those interested will have the opportunity to participate. However, at this moment, we don't have a drug ready for human trials. Please be patient as we're working as quickly as possible. We share your excitement about this work and are fully committed to putting our efforts into it.
We'll keep the patient community updated on our progress!
Glossary:
Association: In the context of DNA, an association refers to a statistical relationship between a specific genetic variant and a particular trait or disease, indicating that the presence of the variant is correlated with an increased or decreased likelihood of the trait or disease.
Regions in DNA: Regions in DNA are specific sequences or segments of the DNA molecule that have particular functions, such as coding for proteins, regulating gene expression, or acting as structural components.
Macrophages: Macrophages are a type of white blood cell that helps protect the body by engulfing and digesting harmful bacteria, dead cells, and other debris.
Pathway:
In a medical sense, a pathway refers to a series of actions among molecules in a cell that leads to a certain product or a change in the cell, often involving processes like metabolism, signal transduction, or gene expression that are crucial for maintaining health and responding to disease.