NEB Podcast #62 -
Transcript
Interviewers: Lydia Morrison, Marketing Communications Manager & Podcast Host, New England Biolabs, Inc.
Interviewee: James Lee, M.D. & Ph.D., Clinician Scientist Group Leader, The Francis Crick Institute
Lydia Morrison:
Welcome to the Lessons from Lab and Life Podcast, brought to you by New England Biolabs. I'm your host, Lydia Morrison, and I hope this episode brings you some new perspective. Today I'm joined by Dr. James Lee, a practicing gastroenterologist and clinician scientist group leader at The Francis Crick Institute. James uses his clinical observations to inform his research around inflammatory bowel disease. James, thanks so much for taking time out of your busy schedule to chat with us today.
James Lee:
You're very welcome. Thank you for having me on.
Lydia Morrison:
Yeah, we're so excited to have you here. I know you have a really strong background in gastroenterology. Could you tell us what led you down that route?
James Lee:
Sure. Well, I am a gastroenterologist. As well as running a research group at the Francis Crick Institute, I'm also a practicing gastroenterologist. I see patients on a weekly basis. I mean, I originally got into gastroenterology mainly because I just think it has a whole selection of diseases that we still really don't understand very well. There are several specialties within medicine where we pretty much know what's going on with the diseases and we have very effective therapies. I think when you think about diseases like Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease, we definitely don't have that. We have drugs that work in some people but not others, and we still don't really understand what's going on. And I think that initially piqued my interest both as a doctor and actually also as someone interested in understanding the mechanisms why diseases develop in the first place. It felt like it was the right place for me that I could work in this area.
Lydia Morrison:
Yeah. How does your clinical work inform your research?
James Lee:
It absolutely informs my research. I mean, I see patients with inflammatory bowel disease. I run a clinic up at the Royal Free Hospital, which is a large tertiary referral hospital in the UK, and I see patients with complex inflammatory bowel disease on a weekly basis. So I see the patients who are facing the sort of challenges that we are trying to fix in the lab, so patients who haven't responded to the medications they've been given, or patients who've had a really challenging course of inflammatory bowel disease and needed operations to have bits of their bowels taken away as part of their treatment.
I see the fact that some of the patients we look after are trying to do things like start their families or settle down, get their first jobs, finish their education, and all of this is being challenged by the fact that they have these incurable illnesses for which we don't have most effective therapy. So it gives us immense motivation in the lab to do the work that we do. It also actually often helps us directly, so we often get samples from the patients who I see in my clinic that we can then actually test to try and reinforce some of the conclusions that we are working towards or to actually test potential therapies to actually see whether or not these would work to control inflammation in patient tissue.
Lydia Morrison:
Wow, that sounds like really powerful tools by having the patient's samples directly available to you and being able to work with those in the lab to find solutions that might work for those individuals. I'm curious, what can genetics tell us about prognosis and disease susceptibility?
James Lee:
So I think the thing about genetics is when I started as a scientist, we probably knew of just a handful of regions in our DNA that are directly contributing to why people get diseases like Crohn's disease and ulcerative colitis. And over the last 15 or 20 years, we've just seen an explosion in the success of complex disease genetics. So for Crohn's disease and ulcerative colitis, we now have over about 400 regions in our DNA that we know of that are directly involved in what's going wrong when people develop these diseases. So there's this immense potential to really better understand the diseases, and we know that if you found a drug and that drug targets a pathway that's implicated by genetics, that drug has a far higher chance of actually ending up working and becoming an approved and effective medicine than if you have a pathway that's a drug targeting a pathway that's not implicated.
So genetics has this huge potential. The big challenge we have is that while we know where in our DNA things are going wrong, we don't know what's going wrong and we don't know how that is contributing to disease, and that's why my lab does the work we do. We specifically use genetics as a starting point to try and understand what's going wrong in diseases and are there better ways we could be treating these diseases.
Lydia Morrison:
So it really sounds like it comes down to the molecular pathways and understanding those molecular pathways as a means of improving treatment. Is that right?
James Lee:
Yeah, that's right. So we start off, we go from all scales. So we go from the genetic scale at a very, almost often a single nucleotide change among the 6 billion letters in our DNA. Single changes can be contributing to why people get diseases. So we focus on finding those. We focus on figuring out at a molecular level what's going wrong at that, when you have that change that then contributes to disease. We focus on not going from that molecular level to a sort of pathway level. We do that, all of that we do in primary immune cells, which are the cells that fundamentally drive the inflammation in these diseases. And then we step further and further away. When we understand what the gene is doing, we understand what the pathway is, we then think about how that pathway could be therapeutically modulated and ultimately take this back to actually having a patient where we could think about a different way of treating their disease.
Lydia Morrison:
You recently published a paper about ETS2 which you found to be a crucial component in inflammatory bowel disease. What was the process of that discovery like?
James Lee:
So we've known for about 15 years that there is a region on chromosome 21 that increases your chance of getting both Crohn's disease and ulcerative colitis. And actually, interestingly, about three or four other inflammatory diseases as well. But no one's really understood what is going on at that region because that region turns out to be what we call a gene desert. It's a region where there are no genes at all at the site of the disease association. So this piqued our interest because these are the sort of regions that often get overlooked when people are thinking about the downstream studies. So we figured that this must contain and enhance one of these regulatory elements. They're a bit like volume dials in our genome that can turn up and turn down gene expression, and they're often located in these regions where there were apparently no genes.
So we figured there must be one of those and that it must be functioning in an immune cell. Enhancers can work differently in different cell types. We figured because it was associated with five different immune diseases, first of all, it tells us that this enhancer is doing something really important, but it also tells us that it's probably doing something in an immune cell. So we started by going looking to see, can we see that there's an enhancer there, and if so, what cell type is it in? And sure enough, we found that there was a very strong enhancer that was specifically activated in a type of immune cell called macrophages. And we know macrophages are really important in inflammatory diseases. In fact, they produce many of the inflammatory chemicals, the cytokines that we target with our current best therapies. So at that point, we then had to say, "Well, what gene is being regulated by this enhancer?"
So through a series of experiments, some of which we actually deleted the enhancer in macrophages and looked to see what genes were affected, others of which we looked to see what region the enhancer physically interacts with. We ended up finding that it wasn't the two nearest genes that a lot of people have thought it might've been, but actually a gene that was located quite a long way away called ETS2. And people didn't really understand what ETS2 was doing in macrophages. So through a series of experiments where we could either knock it out using CRISPR, or we could over-express it, we then actually ended up figuring out that ETS2 was not only essential for pretty much every inflammatory infection we could think about in a macrophage, but it was also sufficient. So in that sense, just turning on ETS2 made resting non-activated macrophages end up looking just like the macrophages that you can find in the gut of patients with diseases like Crohn's disease.
So that got us really excited because among the genes that were being turned on by ETS2 were all the drugs targets that we currently use. So things like TNF or IL-23. So we ended up mapping out how ETS2 does that. We ended up mapping out the situations in which that occurs, and we also ended up showing that this pathway is completely switched on in the macrophages in diseased tissue. And that then led us finally to think about is there a way we could switch it off?
So through a series of different experiments, we identified a small molecule that's currently used for other non-inflammatory conditions, but seems to be able to indirectly turn off the activity of ETS2, and we could show that if you take patient tissue from patients who have active inflammatory bowel disease, that drug was capable of switching off the inflammation in those bits of tissue. So we think we've potentially found a new way and potentially a more effective way because this is the central controller of inflammation that we are now targeting not just a single cytokine at the bottom of the cascade, and we think that this may offer us a new way of treating IBD in the future.
Lydia Morrison:
Wow. That sounds like a really powerful finding in terms of patient care and the drugs available to patients to improve their lives. How do you see your research findings and understanding of this ETS2 molecular pathway? How do you see those findings leading to improved treatment plans for patients?
James Lee:
At the moment, the treatments we have typically target one or two molecules. So they're, for example, monoclonal antibodies against things like TNF. And those treatments do work in some people, but there are some people who lose response after a while, or there are some people who never respond in the first place. And one of the things we've increasingly recognized is that if you target more than one molecule, often that works better than targeting single molecules.
And so the goal for all of this has been thinking, well, given that we know that most of the molecules that we target are produced by inflammatory macrophages, what we'd love to find is the thing that turns on those inflammatory macrophages in the first place. Because then you don't have to worry about targeting all the things that are produced as a result of them being turned on. You just turn them off at the origin.
And that's essentially what we found. We think ETS2 sits at the top of the pyramid. It is sufficient to turn on and make resting macrophages become highly inflammatory macrophages just by being over-expressed. So what we think we may have is an ability to develop a treatment, and the MEK inhibitors that we've shown work at the moment in the lab aren't quite ready to be used in people because they do have side effects. And we're working on ways of making those much more selective and much more targeted. But what we think we have a way now is a way of actually turning off the very origin of what's going wrong in those monocytes, which may then be much more effective because you will have effects across all of the inflammatory cytokines that are being targeted individually at the moment.
Lydia Morrison:
Well, what an important finding the identification of ETS2 has turned out to be, and I look forward to seeing how methods to turn ETS2 off potentially in a controlled way can help these patients and stop the macrophages from sort of entering this disease state. Your work seems to lead naturally into precision health treatments based on patient specific samples and specific DNA differences. Do you think that that's the future of autoimmune disease treatment?
James Lee:
I think it may be part of the future. And I think one of the things that was really striking about this discovery that we made is that for many of the regions in our DNA where there are DNA changes that associate with disease, those DNA changes are uncommon, right? They occur in a small number of people, but they're not in the majority of people. In fact, at this ETS2 gene desert, the disease associated variant is commoner than the non-disease associated variant. And what that ends up meaning is that most patients with inflammatory bowel disease will have this pathway switched on and will have a genetic element to this pathway being dysregulated. And that's really exciting because actually that gives you a potential therapy that for which you wouldn't have to stratify by their genetics because we don't see a difference across people with this pathway because we see that everybody with IBD seems to have the pathway switched on.
So I think precision medicine is an incredibly attractive concept, but it's a concept that arises because of the idea that maybe our medicines only work in some of our patients, and therefore identifying who needs what medicine is the right way to do it. I think the real exciting thing for this particular work is that we found a pathway that seems to be absolutely central to IBD, and in which case, if we can target this effectively, you may not need to stratify. You may have a method of treating IBD that is irrespective of what's the ultimate driver of the inflammation. If you can switch that inflammation off, you may not need to stratify. You may have something that's much more effective. So precision medicine is incredibly useful. I think it's a really attractive thing. It hasn't quite come to fruition in a lot of IBD so far.
I'm really excited about the fact that if you can find the core central drivers, which we can often find by using genetics, then it may actually mean that we don't need precision medicine. Because if you think about it, when someone has a heart attack, you don't need a biomarker or precision medicine approach to decide whether or not you give them aspirin or not, or to give them a statin or not. And that's because these are treatments that are highly effective, affordable, and safe. And actually the need for precision medicine and autoimmunity would go away if you had a treatment that was highly effective, affordable, and safe. And that's what we are now looking to do by targeting the very central pathways that are likely to be going wrong in most patients.
Lydia Morrison:
I think your response to that is really interesting because I agree, precision medicine, I think it's like a really catchy term, and I think it's really important for the treatment of some disease states. But I think you raise a really interesting point in that by being able to distinguish these sort of top tier or instigators of the molecular pathways will allow us to treat a broader group of individuals without the need for precision medicine, but be able to offer new treatment alternatives that are more effective than those that we currently have available.
James Lee:
I think that's absolutely right. And I think as my previous work when I did my own PhD, was looking at biomarkers, I'd probably spend more time thinking about precision medicine, inflammatory bowel disease than most people. I think sometimes you find discoveries a bit like this one region, and we didn't really set out to find a master regulator of information, but when we did find it and we realized it was quite so prevalent as it is, and what we've ended up realizing is that this may be something that doesn't need a precision medicine approach. This may be something that's so central that actually all benefits, all patients could potentially benefit by turning down this pathway.
Lydia Morrison:
Yeah, it sounds like it could potentially have a really huge impact on the quality of life for these patients, and I hope that your group is able to quickly identify some of these therapeutics that might work to attenuate ETS2 and relieve the distress that some of your patients deal with on a daily basis.
James Lee:
Yes, we hope so too. We're working hard to achieve exactly that.
Lydia Morrison:
Well, we very much appreciate you sharing your work with us today and spending time explaining it to our listeners, and we look forward to seeing what the future brings.
James Lee:
That's great. Thank you very much for having me on.
Lydia Morrison:
Thanks so much, James.
Thank you for joining us for this episode of the Lessons from Lab and Life Podcast. Please check out our show's transcript for helpful links from today's conversation. And as always, we invite you to join us for our next episode when I'm joined by Sophie Vaud from UK-based Colorfix, a biotechnology company developing innovative methods for textile dyeing.
