Epigenetics, Inflammation and the Human Immune System

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People with diabetes often have a host of other conditions including cardiovascular disease and kidney disease driven by inflammation. On today's episode, we talk with Dr. Katherine Gallagher, professor of surgery, professor of microbiology and immunology, and the Leland Ira Doan Research Professor of Vascular Surgery at U of M, who is looking at how epigenetics - the influence of environmental factors and behaviors impact on gene expression - might explain changes in the immune system in people with cardiovascular disease, diabetes, and other conditions related to inflammation. 

Transcript:

Kelly Malcom:

Welcome to the Fundamentals, a podcast where we explore biomedical research here at Michigan Medicine. Research is fundamental to University of Michigan's mission to improve the world. On each episode, we'll meet the people behind the research, learn more about their fields and the fundamental questions they are trying to answer.

 I'm Kelly Malcolm, a science writer and communication strategist for the University of Michigan Medical School. This season, we'll start by explaining a little bit of the history behind the questions our experts are asking and get a glimpse into the future of healthcare.

For centuries, diabetes has long been recognized by its noteworthy ability to cause extreme thirst and intriguingly, through the honey-like taste of urine from a person with the condition. As early scientists sought to explain its cause, a young professor named Charles Jacob Marchal de Calvi, presented to the French Academy of Sciences that he was the first to recognize a connection between tissue death or gangrene of the foot and diabetes.

In his book, Recher Sur Les Accidents Diabetiques, published in 1864, he states, "Diabetes creates a tendency towards inflammation and gangrene." But he did recognize that, "We do not know the nature of the state that in diabetes leads to inflammation and gangrene in the tissues. But regarding its effects we are entirely certain in confirming its existence."

Before the discovery of insulin in 1921, gangrene was the second cause of death behind diabetic coma in people with diabetes. While rates of coma decreased with insulin therapy, complications from foot disease went up. Thankfully the discovery of penicillin in 1928 reduced the number of infections and the field of vascular surgery evolved as clinicians perfected techniques to help restore blood flow to the limbs. Still, there are a significant subset of people for whom treatments simply do not work. Their wounds do not heal and for whom amputation is necessary. This early observation of the link between inflammation and diabetes continues to be explored.

People with diabetes often have a host of other conditions including cardiovascular disease and kidney disease driven by inflammation. Our guest, Dr. Katherine Gallagher, professor of surgery, professor of microbiology and immunology, and the Leland Ira Doan Research Professor of Vascular Surgery at U of M is looking at how epigenetics, the influence of environmental factors and behaviors on gene expression, might explain changes in the immune system in people with cardiovascular disease, diabetes, and other conditions related to inflammation. Welcome Dr. Gallagher.

Dr. Katherine Gallagher:

Oh, thank you very much for having me.

Kelly Malcom:

All right, let's dive right in. How did you decide to enter the field of surgery?

Dr. Katherine Gallagher:

Well, so it was for me a little bit more of a complicated path. I was always interested in the research aspect and for a long time thought about doing a PhD or kind of being a purely focused researcher. I always had an interest in medicine and in human disease. However, when I was in my undergrad, I did a shadowing with a physician and so I kind of got hooked and decided I wanted to try to incorporate both things, where I could do clinical medicine and then also impact some in the research space. So I then decided to go to medical school and during medical school I had several other research opportunities that I pursued, one of which was very involved in looking at surgical disease. And I also had a mentor that was a surgeon doing research. And so I was somewhat inspired by her to sort of join the ranks of surgery.

I also liked surgery from a clinical perspective because I got to use my hands, I got to solve problems instantaneously. I got to see the results of what we were able to do. So those were some of the reasons that I found surgery very interesting. And I also liked the research component. So I liked the surgical diseases. I had already started to develop a high interest in cardiovascular disease processes. I had had several family members that were affected by cardiovascular disease and diabetes, so it was somewhat near and dear to my heart. So I also developed sort of at the same time a research interest in some of these common pathologies that surgeons treat.

Kelly Malcom:

So a true clinician-scientist. So the reason I really wanted to talk to you was I was intrigued by the idea of a connection between inflammation and surgery and didn't really understand how those things came together. Can you describe the linkage between them?

Dr. Katherine Gallagher:

Oh yeah, sure. And that's particularly in the cardiovascular and cardiometabolic disease space. If you think about diseases like diabetes or atherosclerosis, things that are commonly studied in the cardiovascular world, those are very much diseases of inflammation where it's been well studied and well described that a lot of the complications related to diabetes are really due to increased or excessive inflammation under various circumstances. And the same is true in a lot of the other cardiovascular diseases.

In atherosclerosis, for example, or in aneurysm formation, some of these common surgical diseases that often involve surgical therapy are actually manifestations of chronic inflammation, where there's too much inflammation and the body can't shut it off appropriately. And so that's what kind of leads to the disease and leads to some of the pathology that we see. So there's a very strong connection, particularly again in that cardiovascular world between these common cardiovascular diseases that we all know, atherosclerosis, which leads to heart attacks or MIs and strokes and things like that. And then diabetes, which leads to things like non-healing wounds, eye disease, kidney disease, some of these other things that we hear about. And that's all really a manifestation of this chronic inflammation.

Kelly Malcom:

So I know that you study this process. What is the main focus of your research?

Dr. Katherine Gallagher:

So the main focus of my research is really on the intersect between immunology and inflammation, kind of where those two worlds meet. So again, like I mentioned before, a lot of the diseases that we look at and that we study in the lab are related to either diabetes or other cardiovascular diseases are all processes that result from excess inflammation.

Now, when we take a step backwards and we look at why is there so much inflammation, why can't the body shut off this inflammation like it should be able to do? And so that takes us a step backwards and then we start looking at the immune system. So a lot of these different immune cells that you may have heard of before, neutrophils, macrophages, T cells, a lot of these immune cells contribute to all of this excess inflammation. And in these disease states, like in diabetes for example, these immune cells get altered and so they can't turn off the inflammation.

They basically continue to produce all of these inflammatory cytokines and kind of flood the body, if you would, with inflammation. And that causes all of these complications that we see from diabetes and some of these other diseases. So my research is really focused on understanding why these immune cells become so abnormal, what is going on molecularly inside of them that is making them sort of misbehave, if you would, or not be able to regulate themselves when it comes to making inflammatory cytokines.

And we're looking at ways to sort of reverse that in these disease states. So we identify, for example, and this may be a little bit more complicated than we want to go into, but we've identified some of these epigenetic mechanisms where basically these genes get altered and they get constantly turned on through a program. So you keep making all of these inflammatory cytokines, can't turn them off. And we're looking at ways to kind of reprogram these immune cells by turning off some of these epigenetic programs or turning them on in some situations, but basically looking at a way to make these immune cells more normal, if you would, or to be able to stop inflammation in the disease settings.

Kelly Malcom:

So that makes me wonder, the diseases that you were talking about, people think of having a strong environmental or behavioral element to them, maybe what you eat or smoking, etc. What is the direction of the effect? Is it, you're doing something like smoking and then that is causing inflammation or is there something in your genes that makes you more susceptible to having inflammation? Have you figured that out?

Dr. Katherine Gallagher:

Yeah, that's a great question and I think it's something that's, to some degree, a combination of both things. So I think at least in our situation when we're looking at the immune cells and what's making these immune cells dysregulated, it is often a combination of some genetic factors. So some people are more susceptible to certain environmental insults than others, and it's also a combination of those environmental insults. So certainly smoking, dietary changes, some of these other environmental factors that you mentioned will initiate some of these epigenetic changes in these immune cells that cause them to be inflammatory.

A hundred percent, we know that, and that can happen in anybody with enough exposure to these certain things, but there are certain people that also are more predisposed to that. So maybe a small degree of smoking initiates these changes and kind of starts this downward negative cascade of inflammation. Whereas in other people, they could smoke for years and years and they don't necessarily have the same downstream effects. So we're also looking at that, and there definitely is a very strong genetic and epigenetic component that kind of work together in some of these things. And some people are just very predisposed to a small environmental insult and they have some genetic programming that just makes them kind of go haywire in the inflammation space.

Kelly Malcom:

So how are epigenetics and wound repair connected? I know that's a focus of your work.

Dr. Katherine Gallagher:

Yeah, so we do a lot of stuff with diabetes in particular, and looking at why diabetic wounds don't heal. And unfortunately most people don't realize it's one of the most common complications of diabetes, results in a very high degree of amputations in the United States. In fact, it's the leading cause of amputations in the United States. And a lot of these amputations that we're performing are strongly associated with significant mortality, actually rates that are worse than most cancers.

And I think most people don't realize that and how devastating diabetes is. But we and other groups have kind of looked at, it's known for a long time that a lot of these immune cells are very inflammatory in the diabetic wound space. And again, it's the same problem that I've described in other diseases where these immune cells just can't turn off the inflammation. And so they continue to make all these inflammatory cytokines, which prevents the wound from healing, which ultimately leads to infection and other things that result in amputation.

So from the epigenetics part, we've identified a few of these epigenetic programs that are altered in these immune cells in diabetics, and we're trying to use nanotherapy or specific cell-targeted engineering therapy to sort of reverse the changes in these immune cells and make them normal again and try to improve the wound healing in the diabetic patients.

Kelly Malcom:

That sounds very high-tech, futuristic. And that's a good segue into what potential therapies are on the horizon for maybe calming some of those immune cells down. How would you go about treating that?

Dr. Katherine Gallagher:

Yeah, so people have started to look at this problem now for at least the last 30, 40 years. And initially it seemed like we could just try to decrease all the inflammatory products, the inflammatory cytokines that are made by these immune cells. But the problem with that is that you need some inflammation to be able to heal the wounds. So in other words, it's sort of like, I always call it like a Goldilocks type effect. It's not all or none. So just shutting down all the inflammation can be bad as well because then you can't fight bacteria or other pathogens. You have trouble healing the wound because the cells aren't responding to normal cues.

So some inflammation is good, but too much is bad. So you're kind of looking for that middle of the road kind of scenario. So our therapies are kind of designed at targeting the specific cells, the specific immune cells that are the bad players here. Because not all the immune cells are bad players, and you need some of them in there, and you need some of them to do the good parts of healing, if you would. So we are trying to target specifically, some of these epigenetic markers that we see that are increased in the bad immune cells, the bad macrophages that we're seeing specifically, and try to reverse those specifically in the wound, in order to improve the healing. So that's kind of what our ultimate goal is.

Kelly Malcom:

So inflammation is one of the institution's research priorities, and it has been one that probably it's so broad, so it's hard to define. Why do you think it's important for us to do more research into inflammation? What is, to you, the role of inflammation and overall well-being?

Dr. Katherine Gallagher:

Yeah, so I think inflammation has been, at this point, linked to so many different disease processes, even beyond the ones that we've talked about here. People are studying inflammation in cancer, inflammation in various neuro diseases. Obviously, it's been well studied in cardiovascular disease and diabetes and some of these other things for a while. But I think people are starting to recognize that it's one of the major drivers and one of the major pathologies that we're seeing in a lot of different disease processes.

So us understanding more about inflammation, even if it's in a specific disease. Even as we understand more about diabetes, some of those things we find there may be relevant to cancer, to other neuro diseases, to other diseases where we see chronic inflammation. So I think understanding some of these molecular mechanisms and understanding what's wrong with the immune system or what's controlling how immune cells behave in various situations will help us in a multitude of different diseases, not just the single individual disease that one researcher is studying, for example.

Kelly Malcom:

Who are your most frequent collaborators, and is there anyone in particular you wanted to acknowledge?

Dr. Katherine Gallagher:

Oh, goodness. Well, Michigan is great with having a lot of people to... It is an absolute team effort, and obviously none of this happens alone or in a silo. So I've been very fortunate to have really great people working in my lab, really great clinical collaborators that have helped me to develop a lot of this stuff and provided me with a lot of the time. And then collaborators sort of all across the university in various disciplines.

I mean, the people now that I work most closely with are some people who have mentored me, Beth Moore and Steve Kunkel, certainly do a lot of work with them. And then current collaborators that I do a lot of work with Johann Gudjonsson from dermatology, and then my own colleagues, Andrea Obi and Frank Davis. So lots of people to thank and they all contribute in unique and interesting ways. And I think that's what makes Michigan to some degree very special, is that you have all of these great minds kind of sitting in different departments or different areas. And I think some of the best science comes from bringing them all together and combining our forces.

Kelly Malcom:

Yeah, that's definitely a through line through most of our episodes is how collaborative U of M is. So it's wonderful to hear. Do you have any advice for maybe a young person who is wanting to get into this field? What do you feel are the great questions that still need answers, that still need people to kind of dedicate themselves to finding out?

Dr. Katherine Gallagher:

Yeah, I mean, I think just developing a question that you're passionate about is probably the most important thing. So whether it be a disease process, whether it be something that you see clinically all the time and just sort of, "How do I solve this problem? I see that this is always an issue and I see patients with X in the hospital." That's kind of really what drives, I think, some of the most impactful research. And for me, it really started with as simple as I didn't like seeing all these diabetic patients getting amputations and then not doing so well.

So it really kind of drove me backwards into, "Well, I'd like to look back and see what are some ways that we can try to understand this disease process better so that we can try to develop better therapies. Because part of the reason that we don't have good therapies for that is because we don't understand the disease process well enough to develop these therapies." So I think to a new person starting out, I'd say, "Find your passion, find a problem that you see that you don't like, that you want to solve." And then start looking backwards at, "Well, how can I constructively try to look at this problem and understand more about it so that we can provide better treatments?"

Kelly Malcom:

And you kind of hinted at my next question, which was, how does your clinical practice maybe affect your research space or your research focus? We don't have a lot of guests who do both. So how does seeing patients maybe affect the way you ask your question or the questions that you even come up with?

Dr. Katherine Gallagher:

Yeah, so I think that's one of the huge strengths of a clinician-scientist is that they see patients. Like for me, I am able to see these patients. I gave the example with a diabetic wounds. So I see these every day in clinic. I'm performing these amputations, I'm seeing the outcomes, the devastating outcomes for patients and families from this, and I see what the wounds look like, and I'm able to sample some of the tissue from them. So that also helps inform the research, that we can take human tissues in human cells and see in real time what are the immune cell problems that we're seeing, and then translate them backwards and say, "Okay, now let's look at them in a more specific fashion and look and identify exactly what's going wrong with these immune cells so that we can try to fix them or make them better."

So I think that is the advantage or the strength, if you would, of a clinician-scientist, is we can actually ask very real-world problems based on diseases that we're seeing in patients with issues. And it exists sort of all across the clinician-scientist space. I'm just talking about basic and translational research, but certainly people who are doing engineering-type research, they can identify, "Well, what are some of the engineering challenges that we're seeing with various devices or things like that, and how can we modify those so that they're more user-friendly or prevent X-complication in patients?" So I think that's really the advantage of clinician-scientists is that they're able to see these problems in real time and then take them back to the lab, try to figure them out, and then try to move therapies forward.

Kelly Malcom:

All right. Well, thank you so much Dr. Gallagher. Again, it's been really great having you on the show and look forward to hearing more from your lab and your work.

Dr. Katherine Gallagher:

Thank you very much.

Kelly Malcom:

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