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Oby: From the campus of Harvard Medical School, this is Think Research, a podcast devoted to the stories behind clinical research. I'm Oby.

Brendan: And I'm Brendan. And we are your hosts. Think Research is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center--

Oby: --and by NCATS, the National Center for Advancing Translational Sciences.

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Brendan: Despite various health benefits of moderate alcohol consumption, there is a fine line before the U-shaped curve brings on detrimental inflammatory effects from alcohol in the liver and other major organs. The research shows that chronic liver inflammation is a catalyst for liver fibrosis and other irreversible forms of end-stage liver disease.

For her entire career, Dr. Gyongi Szabo has worked across the translational spectrum to better understand and improve treatment for this deadly condition. Gyongi Szabo is the chief academic officer at Beth Israel Deaconess Medical Center and professor of medicine at Harvard Medical School Dr. Szabo, thank you for joining us. And welcome to Think Research.

Gyongi Szabo: Thank you, Brendan. It's a pleasure to be here today.

Brendan: You're the chief academic officer at Beth Israel Deaconess Medical Center. And you're also a researcher, and your research is focused on the health impacts of alcohol. How did you become interested in this area?

Gyongi Szabo: So yes, I am a chief academic officer, which means an administrative opportunity to increase the research at Beth Israel Deaconess Medical Center. But I'm personally very much invested in this as a scientist myself. I was able to bring my laboratory here to BIDMC, and our lab is interested in the health effects of alcohol, but particularly the effects of alcohol on the liver, if it relates to alcoholic liver disease and alcoholic hepatitis.

For many years at the beginning of my career, I studied the effects of alcohol on the immune system. That turns out to be fairly substantial. Particularly excessive drinking-- binge drinking or chronic alcohol use-- has different subclinical immunosuppressive effects on the immune system and immune responses in general.

We also found out from our studies over time that binge drinking, as well as the sustained larger amount of alcohol consumption, actually increases inflammation throughout the entire body. And not only in the liver, but many other organs are affected, including the brain. And that chronic alcohol use actually induces neural inflammation that is believed to contribute to some of the addictive components of alcohol and also to alcohol-related cognitive defects.

Brendan: And you mentioned you began studying alcohol and the immune system. And I wanted to ask you about your training, if you could tell us a little bit about your path to research, because it was not the traditional research path that most people are familiar with.

Gyongi Szabo: Yeah, so I'm a foreign medical graduate. I went to medical school in Hungary. And during medical school, I became very much interested in research. In fact, I had opportunities to do some research as a medical student. And that was mostly focused on immune functions and particularly innate immune monocyte and neutrophil functions in autoimmune diseases and systemic lupus and also in rheumatic arthritis.

And that kind of increased and triggered my passion for research. And after finishing medical school, it was clear to me that I wanted to be a physician-scientist. And in order to get more research opportunities, I actually accepted a position at the University of Massachusetts Medical School less than a year after finishing medical school in Hungary.

So moved to UMass to pursue research that was related to immunosuppression and immunosuppression caused by trauma and major surgeries. And that discovery and that postdoctoral fellowship certainly helped me to continue on my research training and also to launch my independent research.

Brendan: And during your postdoc, your mentor-- you were looking for something a research project, sort of research focus. And your mentor suggested studying the effect of alcohol on the immune system of people with traumatic injuries. Can you tell us about how your mentor influenced your research for your postdoc, and how that continued to influence your future work?

Gyongi Szabo: Absolutely. So my mentor, Carol Miller-Graziano at UMass, was an immunologist. And she was very much interested in cytokines and the role of cytokines in post-trauma immunosuppression. This was back in the very late '80s, early '90s, at the time when some of the cytokines-- tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8-- were discovered.

So it was actually a very exciting time. And we did essentially translational research by studying these various cytokines in patients who were after trauma and trying to correlate clinical outcomes with the differences in these serum cytokine levels, but also mechanistically try to find out what is the source and regulation of these cytokines.

So I spent about two, two and a half years working in this laboratory, publishing papers in this area. And my mentor became aware of the grant possibilities through the National Institute on Alcoholism that essentially was looking for new investigations in alcohol-related research. And so it was her idea to kind of ask me to look into the potential effects of alcohol in these trauma patients.

And in fact, when we started to sort out patients who were admitted to the emergency room with a detectable blood alcohol level compared to those who had no alcohol history, we indeed found that the cytokine profile of these patients and the function of their certain immune functions, particularly monocytes, were different, suggesting that perhaps alcohol has an effect on these functions.

And essentially, this whole idea and the hypothesis that alcohol may affect the immune responses in response to, for example, trauma injury, it became the kind of lead hypothesis in my first grant. And I was very fortunate, I think, to be a recipient of a-- in those days, there was a career development award that provided a 50% support for my salary, and allowed me to hire a technician, and essentially for five years establish my own line of research.

And frankly, I personally had some questions that, well, does alcohol can really affect the serious immune functions? And as we kind of started to ask these question scientifically and with rigorous studies, sorted out the various cellular functions, indeed, became more and more convinced that, yes, indeed, alcohol has substantial effect on immune responses. And that line of investigation became my first R01 that launched my future as an independent investigator.

Brendan: So tell us a little bit more about that first grant and what it was like getting that first grant.

Gyongi Szabo: Well, it was fantastic because it allowed us to really ask questions. And I think just the whole idea and the excitement of becoming an independent investigator is a milestone, I think, in everyone's career. I was also fortunate that over time, actually, I was able to go back and do a residency and fellowship training.

I did a fellowship training through the American Board of Internal Medicine Physician-Scientist Training Pathway that allowed me to spend some time in the laboratory, parallel-- kind of alternating between clinical rotations and being in the laboratory. And in that way, I was really fortunate that I could maintain my research laboratory and do my internal medicine and GI fellowship training over a period of six years. That finally led me to have a "-cology" because I realized that studying alcohol and having the immunology background, that interest in immunology, could be a very good sort of merge of fields bringing immunology knowledge to deliver.

In those days, in the early 2000s, there was very little understood about the role of the immune system and the inflammation in liver diseases. And that exactly became the focus of my next phase of research. And in fact, I think that now nobody would question whether inflammation in the liver is an incredibly important component to any sort of chronic liver diseases.

Brendan: Yeah, I think you hear about alcohol and inflammation. A lot of times you hear on the news or in studies about how alcohol reduces inflammation to certain levels. But from work that you've done, you've found that there's a tipping point, correct? There's sort of a point at which there's inflammation-reducing effects, but then when you increase alcohol use, you create inflammation. Am I right about that?

Gyongi Szabo: Well, you are right. So this is what people refer to as the U-shaped curve related to alcohol, alcohol use. And it's particularly true for the general health effects of alcohol. So in many studies, particularly in cardiovascular diseases, but even in overall survival and life expectancy, it has been shown that small amounts of alcohol actually appears to have some beneficial effects, but alcohol use generally defined as about five drinks a week for men, and maybe less for females. Above that is a potential health risk.

And I think the exact amount of alcohol that is safe or not safe really is hard to tell because it depends on the individual's, probably, genetic background and other kind of comorbidities. But definitely, excessive alcohol use and binge drinking is associated with adverse clinical outcomes, whether it's cardiovascular disease, liver disease, or any kind of other actually diseases, and survival.

Brendan: So let's talk about the main focus of your research now, liver disease and inflammation. You mentioned a little bit about the fact that nowadays there's no question that this is an important area. One area that you study is clinical alcoholic hepatitis. But can you tell us about that and some of the other areas you look at in terms of liver disease?

Gyongi Szabo: Absolutely. So in general, we're interested in inflammation in the liver. And the reason for that is because it is pretty obvious by now that chronic inflammation in any kind of chronic liver disease is a trigger and a fast-forwarding kind of mechanism for reaching an end-stage liver disease status, which means that the liver, in response to this ongoing inflammation, develops fibrosis. And over time, fibrosis becomes cirrhosis, which is kind of an end-stage liver disease.

Studies, particularly from some of our and others' previous kind of investigations, revealed that, for example, in chronic hepatitis C infection, the inflammation and fibrosis actually could be reversed if the initial trigger, such as the hepatitis C virus, is removed. Now, that's true to a certain extent until cirrhosis develops. Once there is this final stage of liver damage such as cirrhosis, then we believe that that is irreversible. But prior to that, there's a long period in chronic liver disease where sustained inflammation perpetuates the fibrosis and drives the continued damage to the liver and fibrosis.

So there are multiple triggers for this. And most recently, we are studying two different entities. One is that called non-alcoholic steatohepatitis. And essentially, this is a disease that is a result of liver manifestation of the combination of the metabolic syndrome. That would include obesity, type 2 diabetes, or insulin dependence, and high blood pressure and high and abnormal lipid profile.

And as you probably heard, this is a very common entity in the Western world. And in fact, now it's not only in the Western world, but pretty much around the entire globe with the increased incidence of obesity and type 2 diabetes. So this non-alcoholic fatty liver disease is the liver manifestation of the metabolic syndrome. And in fact, it's the most common liver disease nowadays. Now, it's interesting because--

Brendan: Sorry to interrupt. So fatty liver disease, this is sort of like a lifestyle disease. People eating-- it's related to diet and physical activity level. It's sort of just lifestyle factors that contribute to it.

Gyongi Szabo: So it's yes and no. There are certain forms of this fatty liver disease that could be genetic at a small percent. Then it's also known that there are certain genetic predispositions for developing the disease in the setting of diabetes and obesity. But the majority is lifestyle.

And in fact, changes in lifestyle, losing weight, can reverse some of the processes in this non-alcoholic fatty liver disease. And then what we learned is that the fat deposition in the liver itself may not be as detrimental than too much fat, and that can induce and trigger inflammation. And once there is inflammation on the top of fat in the liver, that is really the critical point where we get concerned about progression of disease.

Brendan: Right. So it's the fat around the liver contributes to inflammation, which sets off this chain reaction of--

Gyongi Szabo: Exactly. And in fact, the fat gets deposited in the liver cells, in the hepatocytes themselves. And sometimes that can cause, essentially, death of hepatocytes. A certain type of death pathways are induced, that then these damaged and dying hepatocytes then can turn on the immune response, essentially recognizing these damaged cells as a danger signal to trigger inflammation. So it kind of creates a vicious cycle that could go down over time, and we're talking about decades when the progression of liver disease can happen.

Brendan: So that's the non-alcoholic liver disease. And then you also look at alcoholic liver disease, or alcoholic hepatitis. Tell us a little bit about that and the clinical trial that you have going on to investigate some ways to treat or-- I know you're looking at biomarkers to identify the level of disease progression. So tell us a little bit about that.

Gyongi Szabo: Yeah. So we became very much interested in the alcoholic hepatitis. So this is a liver disease caused by excessive alcohol intake. And typically, it happens in people who drink alcohol excessively for a kind of sustained period of time. This can happen in people who don't have any chronic liver damage, like cirrhosis, and just freshly develop this acute state of inflammation.

So the acute alcoholic hepatitis is characterized by an acute state of inflammation-- not only the liver, but systemically-- and also with people turning jaundiced, so kind of yellow. That yellowing of the eye and the skin can happen. And once people present with this sort of symptom complex that constitutes for the acute alcoholic hepatitis, the mortality of this condition, dying from this, is somewhere between 30% to 80% likelihood.

Brendan: Wow, and that's within one month of diagnosis?

Gyongi Szabo: Yes, which means that within one month of diagnosis, there is about the 30% to 80% chance of dying depending on the severity of this condition. So if you really think about it, this is a really, really bad diagnosis, because some of the stage IV cancers don't have this extent of mortality.

And the most striking component for this is that, in spite of the severity of the disease, we really don't have good therapies. We give patients steroids with the idea that that can reduce inflammation. But the steroids have a moderate benefit, and the benefit of the steroid is only short-term survival and not a h term survival of these patients.

So for that reason, we are very interested in understanding the disease at the mechanistic level, from the standpoint of what cells are playing a role and what kind of signal transduction pathways play a role here. And from those studies, we identify that this intracellular inflammation triggering a receptor complex that's called inflammasome plays a crucial role in sustaining inflammation. And it turns out that the inflammasome plays a very important role in processing some of the cytokines, particularly interleukin-1, that plays a role in perpetuating inflammation.

Interleukin-1 can also increase hepatocytes to die from various stress signals. IL-1 also has a negative effect on liver regeneration. That is a key element in recovery from alcoholic hepatitis. And IL-1 also increases the fibrotic process. So for that reason, we hypothesize that by blocking IL-1 could be beneficial in alcoholic hepatitis, and years ago performed studies using a IL-1 receptor antagonist to recombinant protein called anakinra, which happens to be a drug that is approved by FDA for rheumatic diseases.

So in a mouse model of alcoholic hepatitis, we actually were able to rescue mice from this alcoholic hepatitis. And then through a grant application that was submitted and now supported by the National Institute of Alcoholism and Alcohol Abuse, we are performing a multicenter clinical trial in patients with severe alcoholic hepatitis to test the efficacy and the safety of intervention with this IL-1 receptor antagonist, anakinra.

Brendan: Wow.

Gyongi Szabo: We are very excited about this because this really is a kind of perfect example of translational research, that in our laboratory, people were able to identify a biological molecular pathway, that then in a preclinical animal modality, we were able to target and show efficacy, and now bringing that to a clinical trial in human patients. And in an earlier small study that was already completed, we found that this administration of the IL-1 receptor antagonist was safe in these patient populations. And the reason why it's very important because this is a patient population that, as I mentioned earlier, is immunosuppressed to a certain extent from alcohol.

Brendan: So it kind of brings it all together.

Gyongi Szabo: Right. So we were very nervous at the beginning that by inhibiting inflammatory pathways, are we going to potentially increase the rate of infection and susceptibility of infection in these patients? And the good news is that, no, we didn't see any difference in the infection rate between those who receive standard of care compared to the IL-1 receptor antagonist.

So we are very optimistic. And certainly, those studies are still ongoing to find out the biological effects, because definitely there is a very clear need for some new drugs for this patient population. So we are very excited about the further exploration of inhibiting IL-1 one in alcoholic hepatitis.

And it turns out that one of the large pharmaceutical companies that has an anti-IL-1 blocking antibody also started a large clinical trial in Europe in patients with alcoholic hepatitis to test their own drug. So it's going to be very interesting because there are some differences between that particular trial that inhibits IL-1-beta, as opposed to the trial that we are conducting with the anakinra, because it turns out that anakinra blocks the receptor, and therefore blocks the effects of both IL-1-alpha and IL-1-beta. So there might be differences. But certainly, we're going to find out from the clinical trials.

Brendan: Wow, that's really exciting. And do you know when the European trial is ending? Are your two trials running concurrently? Or is there a gap there?

Gyongi Szabo: So the European trial might be completed sooner than our current clinical trial here in the US. The NIA-supported trials tend to be a little slower. And certainly, the COVID pandemic didn't help our enrollment.

You also asked about biomarkers. So as part of our multicenter clinical trial of this alcoholic hepatitis patient population, we also have an aim to look for new biomarkers. That would be essentially a liquid biopsy approach to learn more about predictors of disease and predictors of response to therapy. And in that area, we are doing various studies on the proteomic analysis and micro-RNAs in particular as potential biomarkers in this patient population.

Interestingly, we also found that alcohol increases the production of extracellular vesicles, particularly exosomes, that are tiny vesicles that contain unique biological information from damaged cells. And that's another line of investigation for us, to identify the cargo of these extracellular vesicles, particularly exosomes, with respect to protein cargo and micro-RNA cargo. So those studies are ongoing.

Brendan: So I want to ask you about sort of your role. We introduced you as chief academic officer. You're obviously very interested in research, and that's the focus of your career. And you're also now in a senior leadership role. You serve as a mentor to many different people. What would you say that you bring to your role as a physician-scientist who has been deep in research for as many years as you have?

Gyongi Szabo: So I was excited to take on this chief academic officer role at BIDMC because I thought it kind of brings together the various lines of experiences I had throughout my career as a physician-scientist, and also as a leader. So before I came here, I was the director of the MD/PhD MSTP program at UMass. That essentially is the training of physician-scientists. And that was a tremendous opportunity to not only just to build a program, but to really work with our MD/PhD students who then hopefully become successful independent investigators and physician-scientists at various institutions around the country.

So this kind of appreciation for the education opportunities for physician-scientists is definitely something that I have a long roots and certainly advocate for. So I believe that in my role here at BIDMC, where I oversee research as well as educational activities-- we are interested in potentially establishing a training pathway that would particularly help those who are physicians but want to be more involved in research to launch them on a career at the phase of postgraduate training.

I also served as vice chair for a large department of medicine before I came to BIDMC. And in that role, I was very much involved in recruiting new scientists and also supporting our existing scientists with various core resources, such as core facilities, identifying new methodologies that should be established at the institution to enhance the technological repertoire of our researchers. And these are certainly areas that I'm involved in now.

I've been in this position for 18 months. And back in November, we completed a long process of strategic planning for BIDMC. So this was our InSPIRE BIDMC plan. That stands for Institutional Strategy Plan for Innovation, Research, and Education.

Brendan: There you go. You got the acronym.

Gyongi Szabo: And so now we are going on to the implementation of the InSPIRE plan. And hopefully in the next five years, we can follow the steps to expand research, create unified platforms in -omics technologies-- that was part of our goal for the future-- with very strong bioinformatics support and the various transcriptomics, genomics, and glycomic technologies to bring that all together in a new pilot project and some translational research hubs that we want to create here at BIDMC.

Brendan: Yeah, it's so interesting, because Boston has so many great research institutions. What does it feel like to be leading the charge at one of the institutions in Boston, where there are so many?

Gyongi Szabo: So it's a tremendous honor and privilege, and a tremendous pressure to a certain extent, in a good way. We recognized the richness of the environment, and we definitely want to build on strength of our allies and collaborators and the Harvard Medical School.

But definitely, this super environment, at the same time, brings up the challenges of how to differentiate ourselves from our neighbors, and how to gain both local and International attention in a way that we still can relate to ourselves as BIDMC and don't necessarily just get under the entire umbrella of the Harvard and Longwood Medical Area. So part of my job is to head the institution, to increase our alliances and collaborations with our potential partners and collaborators, but at the same time find a niche that that would make us more known and attractive to outside investigators, entities, patients, and researchers as well.

Brendan: Great. And just to finish up, you mentioned earlier that when you started out studying alcohol and liver disease, you weren't sure if there was anything to it. You weren't sure if looking at alcohol and inflammation, if that was really a worthwhile path. But you ended up finding correlation, and it set you off on your research career. And I think it's become your passion now. What would you say to trainees or young researchers who are struggling to identify a passion or not sure where their career is going, how to find that path that's going to provide a research career?

Gyongi Szabo: So I think it's a kind of tricky thing. And I always told this to MD/PhD students or applicants. Because when you go to apply for a school or a position, you have to kind of identify yourself with a particular interest.

But I think, particularly for graduate school and those who are at the beginning of their science career, it is very important to be open-minded and be open to challenges and opportunities, because I think most people don't necessarily know. And even if you know what you like, you should have an open mind about possibilities, because new areas could come up. And in fact, you may find that the most successful or most exciting thing is outside of your current area.

And I think that's very important, particularly in graduate studies, to be willing to take on challenges. Of course, one has to be lucky and also has to be selective. And if something doesn't go the right direction, then have the courage to give it up and start something new, because I think that that could be major dividends over time.

Brendan: Well, Dr. Szabo, thank you very much for joining us. It was a pleasure to have this conversation with you.

Gyongi Szabo: Well, thank you so much. I really appreciate the opportunity to chat.

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Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes and help us spread the word about the amazing research taking place across the Harvard community.

Oby: To learn more about the guests on this episode, visit our website, catalyst.harvard.edu/thinkresearch.

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