Understanding the Immune System with Stephanie Eisenbarth, MD, PhD

Erin Spain, MS [00:00:10] This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Treatments that redirect the immune response, such as vaccines, have saved countless lives and transformed the health of generations. But scientists who study the human immune system’s role in health and disease say there is potential for many, many more such treatments. The new Center for Human Immunobiology at Northwestern University Feinberg School of Medicine has been created to translate innovative science into cures for immune-regulated diseases. Dr. Stephanie Eisenbarth is leading the center. She's an immunologist, and allergy scientist, and has also been named Chief of Feinberg's division of Allergy and Immunology. She joins me today to talk about this new center and her research. Welcome to the show. Dr. Eisenbarth.  

Stephanie Eisenbarth, MD, PhD [00:01:10] Thank you. Thank you for having me.  

Erin Spain, MS [00:01:12] Well, before we get into your work here at Northwestern, tell me a little bit about your path to becoming a physician scientist, how did you get to where you are today? 

Stephanie Eisenbarth, MD, PhD [00:01:21] Sure. So I always say to, especially mentees, that every physician scientist has their own path. And everyone is unique in this career. It's an amazing career. But it's also one with many different twists and turns, and mine definitely had twists and turns. So I started out as an MD-PhD student at Yale, amazing training. But I was pretty sure I was going to be a pediatrician, running a free clinic somewhere not really doing science, that was kind of the original plan. But I had an open mind. And so I wound up in like most MD-PhD programs, you take a break through your medical training in the middle, and I did my PhD with Kim Bottomly, an amazing mentor, who taught me really amazing beauty of the immune system. We studied asthma and allergies, a field that even to this day still remains mysterious. And I fell in love, I fell in love with doing science. So at the end of that time, when I went back to medical school, I had to figure out how I was going to do all of these things, right, I was going to do the science and do the clinical. And it took me a little bit of time to find my path. And I wound up choosing an unusual career path in the clinical side, clinical pathology. It's a subset in the field of pathology, but it's very mechanistic based. And through it, I was also able to continue to do research. So it's a very research-heavy field within medicine. And so that led me ultimately to my first faculty position where I was really able to do fun, exciting, mechanistic science, while also thinking about questions from the perspective of unknown mechanisms in human disease. And so it's been an amazing and fun period that got me to this point. I now actually run a division of allergy, which is a little bit unusual. But again, that twist and turn made sense, because that's where a lot of my research has focused. And so now I'm getting to think even more deeply about many of the allergic diseases out there through the division that I run. And the lab that I run. 

Erin Spain, MS [00:03:09] Let’s talk about the immune system. Describe the immune system to me and how it impacts really every disease process. 

Stephanie Eisenbarth, MD, PhD [00:03:16] I always say I'm biased in this regard, but I do think it impacts pretty much every disease process and health obviously. We think a lot about that in this day and age with vaccines and with immune response, obviously to viruses. So the immune system really sets the tone, the homeostasis of the body. It's your first line of defense in many ways, along with the barrier systems in the body. It keeps you from getting all the infections that are out there that could possibly happen from a prick of a thorn to ingestion of something that's infected, right? If you're eating something, all of these things have, you know, bugs in them. So whether they're viruses or parasites or bacteria, and many times you don't even know the immune system’s saved you. It's protected you right. So it's quick, efficient, and it usually can deal with most of what's out there. The immune system sometimes causes us pain and suffering. For example, when you have an overabundant immune response to something like a pathogen, and that's when we realize we have flu-like symptoms, and we're miserable. But that's the immune system acting to protect us. But beyond that, the immune system can also go awry, right. So it can be misled. And we think about that, for example, in disease states, like allergy, which is what I think about, but also autoimmunity tolerance to transplanted organs isn't another one that we think that's important to understand tolerance, actually, to our own microbes. So we have our own microbes that are part of our healthy ecosystem, if you will, inside our bodies, and the immune system and those microbes have a very beautiful intricate dance that keeps everybody in check, right? You don't want too much of an immune response. And you don't want too much of the microbes taking over. So we think about this in many different forums. I think, especially in the scientific community, right now, the immune response to cancer is a really big one because we've learned how to harness that immune system and really unleash it to do amazing things to protect us and eradicate cancers. It definitely touches on a lot of different health states and disease states. 

Erin Spain, MS [00:05:10] So you mentioned treatments for cancer. What other treatments exist to sort of redirect the immune response? 

Stephanie Eisenbarth, MD, PhD [00:05:16] I would say the original one, and probably one of the most important ones in human health, are vaccines. We learned how to harness the immune system very early on before we knew much about how the immune system works. That has led to huge global changes in the kinds of diseases that especially young children are afflicted by. It's enabled generations of children to really grow up without having sometimes these really life threatening disease states. So I think vaccines really are one of the most important breakthroughs. And what's amazing is despite knowing how to vaccinate people, before knowing about T cells, B cells and all those cells of the immune system, we knew how to do it, but we're still learning. I think the mRNA vaccines for COVID were a great example of that. We're still evolving, we're still creating new ways of making vaccines. That really shows the power of what we can do when we harness the immune system to protect us in a number of different disease states, for example, even just an allergy. We know some of the cytokines, some of those molecular mediators that help make an immune response happen, we've identified them and then we've learned how to make drugs that block them. And that has really transformed the lives of patients. And you can say the same thing in autoimmunity, you can say the same thing and skin disease. Same thing in many other disease states where we've identified the targets. We've made very specific drugs. And we've reversed the pathology. It's a pretty incredible area of investigation. 

Erin Spain, MS [00:06:32] And you were brought here to Northwestern University Feinberg School of Medicine to take on a new challenge and lead a new center, which is the Center for Human Immunobiology. Tell me about the center and what you hope to accomplish and what makes it maybe unique from other centers out there. 

Stephanie Eisenbarth, MD, PhD [00:06:50] Yeah, this is a really exciting opportunity. I'm very honored that I was chosen to lead this endeavor. This is a brand new center for Northwestern. We have amazing immunologists across the campus, campuses being Feinberg Downtown, Lurie Children's and also Evanston, there's investigators doing amazing immunology, immunology research across all of these campuses, but there hasn't been a way to unite them. And that's one of the main goals of the center. And the reason to unite immunologists working on brain cancers, to working on skin disease to working on allergies, the reason to bring them all together is that I think in science in general, this is not unique to Northwestern, but everywhere, we can synergize and help each other and make our science better. I think that's one of the first goals. And actually, that's already happening. We launched our website about a month ago. And we already have about 80 to 90 members. And if you look on our website, there's profiles of each of those members, you'll see that they span different departments, different divisions, different topics of what they're working on, and yet are very excited to work together. I think that's one of the things that was really one of my deciding factors about coming is that I heard from many, many different investigators across the campus, they really were excited about this opportunity and excited to come together. And the second goal is then to expand the immunology that's present here, we'll be doing that through recruitment. And we'll be bringing in new faculty. And there's been a very impressive, I think, backing by the medical school to make sure that this is feasible. So we're going to have renovated space, we're going to have the resources to bring in very top level investigators. I think it's an incredibly exciting time.  

Erin Spain, MS [00:08:19] Describe some of the projects that these investigators are taking on that our community might be interested to hear about.  

Stephanie Eisenbarth, MD, PhD [00:08:26] Sure. I mean, it spans so much. And there's already amazing centers and kind of foci, if you will, across the campus, looking at everything from how does the immune response to HIV work or not work, right? And how does it evolve as you age? There's a very big push recently for us to try to understand aging in general. But within that the immune system very clearly has its own effects with aging, it stops working as well as it does when you're a child. And that has implications for both protection from infection, but also dysregulation, meaning the immune system can then start, unfortunately, attacking yourself. And so understanding why that's happening and how that's happening. And maybe can we do some reverse aging, right, which is a holy grail in many ways, but especially in the immune system would be great. We have people trying to understand how the immune system in the skin is working to both protect us, that's one of your first layers of defense from pathogens, but also from cancers. And then how again, it goes awry and causes disease states in the skin, sometimes very young children, and that sets them up for future problems with dealing with the environment, for example, and this is one of my areas of interest. For example, children who have defective skin barriers can also have increased risk of food allergy, right? You think of that as a gut disease, but they're actually linked. There's so many different amazing, exciting projects, it's hard to list any particular one.  

Erin Spain, MS [00:09:41] Well, as I mentioned, you were also named the chief of Feinberg's division of Allergy and Immunology when you came here to Northwestern and you have your own research lab, you just alluded to that a little bit, some of the work that you're doing there and I want to shift gears a little bit and talk about some of the other work taking place. Allergy and autoimmune diseases have both really been on the rise in the past 20 years, reaching epidemic proportions here in the US and your work. I'd love to hear more about your work and how it's addressing this issue.  

Stephanie Eisenbarth, MD, PhD [00:10:11] Yeah, obviously, I think this is a fascinating question. And I would argue that we've learned so much about the immune system and how it works to fight pathogens, how we can capitalize on it to make vaccines and to fight cancer, to make it tolerant of things like your own self molecules and autoimmunity, and transplanted organs. But we still don't understand some very fundamental aspects of why people develop allergies. And there's many different types of allergies. And each of those different disease states have different pathophysiology. So they have different types of cells that are operational, different reasons that the cells are doing what they're doing. And so we really started to tackle this in the area of food allergy. So as you pointed out, you know, when I was in school, I used to bring peanut butter and jelly sandwiches to school all the time, and now I can't obviously give those to my kids to take to school, because of the rise of specifically peanut allergy, which can be life threatening, right? And so just thinking like a parent, you can imagine how frightening it is to have a child who could have a potentially very severe reaction to peanut to go out into the world where there's peanut proteins everywhere, right? It's not just in a peanut butter and jelly sandwich. So we're trying to understand why those children make that response at a cellular level, specifically focusing on what are the cells of the immune system that make the antibodies that cause that allergic reaction? So IgE is the culprit, we usually think about; that's an isotype of antibody that causes these kinds of massive reactions, and what are the cells that make it and how do those cells get essentially tricked into making it to these allergens? So why do most of us walk around eating peanut butter and jelly sandwiches, but some people can't? Some people are very highly sensitive to it. So it's a fundamental question. And like I said, there's been great research on this for decades, but we still don't have some very, very important answers. So we're trying to understand that. And I would say also, we're trying to understand the flip side of that, which is sometimes the immune system still gets tricked into responding to allergens. But actually people tolerate those allergens just fine. They might not even know that they've made an immune response to the allergen. And that is a huge opportunity for us to understand why particular patients are tolerant to allergens, because they may teach us, how can we subvert the immune reaction in those kids, for example, that have food allergies, how can we make them now tolerant? And so we're trying to understand this at the level of the immune system, which goes beyond the T cells and B cells that everybody thinks about, we think about dendritic cells. And we also think about how the gut itself and the epithelium there are responding to those allergens. 

Erin Spain, MS [00:12:36] Another way that you're tackling this issue is some of the research that you're doing on a genetic form of allergy and a rare group of patients that have a deficiency in a molecule called DOCK8. Tell me about this work and why you study it. 

Stephanie Eisenbarth, MD, PhD [00:12:49] So most allergic disease, like most immune mediated diseases are polygenic, meaning multifactorial. So it's environment with genes, and it's usually multiple genes, not just one. Some patients, unfortunately, who are afflicted by a monogenic form, meaning one gene essentially causes a severe form of a particular disease. This is true in immune-made diseases and other diseases. But by studying those patient populations, we've learned a tremendous amount about how the immune system works in people who don't have those genes. DOCK8 is an example of that. So again, it's a monogenic form of allergy, meaning these patients, almost all of them have pretty severe allergies, in particular, food allergies. Again, very, very rare. But by studying them and actually making mouse models to replicate that gene defect, we've been able to really understand the mechanism that drives that severe form of allergy. And it's led us to understand and identify new cells and new pathways that we wouldn't have otherwise looked at. And the importance to that is by then finding those pathways, discovering those pathways, for example, we discovered a new type of T cell that's very important for IgE, the antibody I told you about that's important in allergy. We call these cells Tfh13 cells. But we discovered these cells, really, because we were able to model this disease. And then when we went back and looked at patients who don't have DOCK8 deficiency, they have garden variety, food allergy, or they have asthma and airway allergy, they also had these cells, but they're a very, very rare population of cells. So it wouldn't have been something we would have looked for otherwise. And so that's an example of where gene defects teach us about regular pathways that are operational, usually in combination with a bunch of other pathways that are helping cause disease, and therefore, again, new targets for us to try to reverse. 

Erin Spain, MS [00:14:37] How do you plan to expand this research now here at Feinberg? 

Stephanie Eisenbarth, MD, PhD [00:14:41] Yeah, one of the reasons I was very excited to start here is that I get to interact with an amazing group of clinicians and physician scientists doing really cutting edge translational work. I really wanted to bring the work that we've done in these preclinical models forward into patients and to understanding how they correlate or don't correlate in human disease. I think that's a very important aspect of doing these animal models. They teach us so much, but you need to understand where it applies and where it doesn't apply, and then how to apply it. Right? Just because we can discover this in a system doesn't mean we know then how to translate it. And so we are working already, probably within the first couple of months of getting to campus, we’re already working with a number of investigators across the campus to try to study patients with allergies, and to try to get at how what we've discovered, these mechanistic pathways, how they translate into human condition. And then can we find ways of again, interrupting them. So that's, I think, really exciting. 

Erin Spain, MS [00:15:37] So we might see some clinical trials soon? 

Stephanie Eisenbarth, MD, PhD [00:15:39] Yes, soon is relative always in research, it takes longer than any patient wants. And I understand that, but it is where we're headed. It's where our sites are.  

Erin Spain, MS [00:15:46] Your lab is also interested in immunology and transplant tolerance. Tell me about that. 

Stephanie Eisenbarth, MD, PhD [00:15:52] I've talked already about understanding tolerance to allergens. But we actually also try to understand tolerance to red blood cells. So this is the most common transplant done in patients are actually red cell transfusions. And it turns out, the red blood cells have all of these molecules on the surface that are polymorphic, they're different between you and I, right? And so we match for a number of these things and make sure that people are going to have a safe transfusion. But then there's hundreds of other molecules that we could react to. And actually, we only understand some very basic at a basic level, why some people respond to those and other people don't sounds very similar to what I told you about with allergy, right? And so that has led us into a really exciting area of research that’s also expanded greatly since coming to Northwestern working with incredible investigators to try to understand how the immune system in the spleen works to regulate this, including in humans, which is actually a huge challenge. And I really, up to this point, have not been able to tackle it. But now with the incredible investigators here at Northwestern, we're tackling it. It's very exciting. 

Erin Spain, MS [00:16:47] Who are you working with on that project? 

Stephanie Eisenbarth, MD, PhD [00:16:49] Yeah, so a number of investigators from pathology from GI. From Lurie Children's …  has been an incredible collaborator who's bringing on spatial transcriptomics to the school and really helping us approach that in a way we would never would have been able to do before. Sam Weinberg is actually a clinical pathology resident, but he's been incredibly helpful with Christi Walniack to help us try to understand the structure of the human spleen, really a very fundamental question. This is the largest secondary lymphoid organ in your body. And it turns out we know very little about how it's structured in the human spleen. Most of what we know is from mouse models. And so this is a really exciting area that we're starting to delve into. 

Erin Spain, MS [00:17:26] One of the goals of your lab is to also be recruiting students and investigators into fellowship programs, funding early stage research. Tell me about your passion and helping these younger scientists who are coming into your lab. 

Stephanie Eisenbarth, MD, PhD [00:17:39] Yeah, I think in the popular press, maybe in the media, people don't understand how much of a community a lab is a research lab. I think they think of, you know, dorky scientists with a notebook in a corner by themselves. And that's absolutely not the case. It really is a group effort. We pass on knowledge, we share knowledge, we challenge each other. That's the job of scientists, right? To help us expand our thinking, our potential hypotheses, right? Some of the most exciting times I think in science are when we discover something unexpected or even maybe are pushed to think about something unexpected, and then go on and test that. And we only do that as a group—a diverse group of investigators, thinking about this from multiple perspectives from multiple walks of life or multiple training points of view. One of my great idols in immunology, Charlie Janeway, always said that some of the best questions he ever got from was, during lectures, he would lecture to the students, and they would ask him questions that were fundamental and he had to admit he didn't know the answer to, and I think that is a really great guiding principle. So I love having trainees from, again, pretty much all walks of life and stages of their training. We've had high school students, we've had undergrads, we have graduate students and PhD students, postdocs, visiting scientists, and then collaborators who are also fellow faculty. I mean, it really, it spans the whole gamut. And I'm incredibly fortunate because I get to run my research lab now with my husband. Adam Williams and I both trained together and then went off to have separate labs for about 10 years. And now we're back together. And we are a great pair because we think about science and immunology and immunology questions from slightly different perspectives. So then we get to talk about it both in lab and at home. It's fun. 

Erin Spain, MS [00:19:14] Science is a family affair for you all. 

Stephanie Eisenbarth, MD, PhD [00:19:17] Including the lab, including the lab. I think that's an important piece to all of this. It's not just we come into lab, we do our own individual experiments, and then we're done. It's discussions. It's doing hands-on experiments together against teaching each other. And actually my lab does that I'm very, very proud of the group that's working together and including my group. I actually have still a group at Yale and we're all still working together, believe it or not, we meet in person and we meet via Zoom. It works.  

Erin Spain, MS [00:19:42] So how are you settling into Chicago? 

Stephanie Eisenbarth, MD, PhD [00:19:44] It's been great. It's busy. So I can't say we've explored Chicago that much yet. But we've had some friends who have helped us do some fun things like take some boat rides and see the city and it's an amazing city. But I think mostly we're focused on making sure our kids are settled, and our lab and our our life here is settled. 

Erin Spain, MS [00:19:59] Well, thank you so much, Dr. Stephanie Eisenbarth, for being on the show today and we're excited to have you here at Northwestern. 

Stephanie Eisenbarth, MD, PhD [00:20:07] I'm really excited to be here. Thank you so much. 

Erin Spain, MS [00:20:19] Thanks for listening and be sure to subscribe to this show on Apple podcasts or wherever you listen to podcasts, and rate and review us. Also for medical professionals, this episode of breakthroughs is available for CME credit. Go to our website, feinberg.northwestern.edu and search CME.