Epigenetic Regulation of Immunity with Dr. Andrew DiNardo

The immune system adapts to various threats through innate and adaptive responses, utilizing epigenetic mechanisms to regulate gene activity without changing DNA sequences. These mechanisms help maintain long-term immune phenotypes, allowing the immune system to respond to changing environments. In innate immunity, epigenetic changes enable immediate pathogen responses, while in adaptive immunity, they create memory cells that remember past infections for quicker, stronger reactions. This adaptability ensures ongoing protection and highlights the potential for developing targeted therapies to modulate the immune response, offering more effective treatments for various diseases.

In this week’s episode of the Everything Epigenetics podcast, join me and Dr. Andrew DiNardo as we explore the complexities of the immune system. Dr. DiNardo shares his journey from internal medicine to addressing global health issues like tuberculosis and his latest research on the impact of school deworming initiatives on vaccine efficacy in children with schistosomiasis.

We dive into how the immune system interacts with DNA, focusing on CD4 T cells and DNA methylation, and discuss Dr. DiNardo's pioneering use of single-cell technology to study immune responses. This technology highlights both the benefits of vaccines and the risks posed by severe infections to our genetic makeup. Our conversation also covers the potential of manipulating these immune responses to develop new treatments and the challenges posed by high-resolution analyses in this field.

Wrapping up, we reflect on the dual role of mTOR in modulating the immune response and influencing DNA methylation patterns. Dr. DiNardo's insights emphasize the complex interplay between genetic regulation and immune function, emphasizing the need for comprehensive data repositories to advance infectious disease research. 

In this episode of Everything Epigenetics, you’ll learn about: 

• Current research on co-infection and immunity
• Immunity through the lens of epigenetics
• Analyzing immune cell subsets in epigenetic studies
• The double-edged sword of epigenetic immune modifications
• The impact of tuberculosis on epigenetic aging
• DNA methylation, cellular senescence and premature epigenetic aging
• Manipulating metabolism to improve epigenetics
• mTOR and its role in immune response
• The potential of carotenoids in preventing epigenetic changes
• Metformin studies in infectious diseases
• The power of food in improving health
• Cutaneous spectrometers

Where to find Andrew:
Baylor College of Medicine profile

Andrew attended Wayne State School of Medicine from 2003 to 2007. His internship and residency in global health and Internal medicine was completed at the Hospital of the University of Pennsylvania in Philadelphia from 2007 to 2010.

Transcript

Speaker 1: 0:01

Welcome to the Everything Epigenetics podcast, where we discuss DNA regulation and the insights it can tell you about your health. I'm Hannah Wett and I'm the founder of Everything Epigenetics. Today, my guest is Dr Andrew DiNardo. He is an infectious disease specialist investigating immunology of co-infection, tuberculosis, epigenetic, regulation of immunity. Of course, what I am personally most interested in we will be chatting about today HIV and global health, just to name a few of his specialties. We are really going to dive into what we can learn about immunity through the lens of epigenetics. He has a lot of great papers that we're going to dive into and really understand how we can apply these and push these to application in real world case scenarios. A quick introduction to my guest.

Speaker 1: 0:58

Andrew attended Wayne State School of Medicine from 2003 to 2007. His internship and residency in global health and internal medicine was completed at the Hospital of the University of Pennsylvania in Philadelphia from 2007 to 2010. He practiced primary care in an underserved community in Southwest Philadelphia from 2010 to 2012 and completed an infectious disease fellowship at Baylor College of Medicine. Andrew has been studying tuberculosis immunology and epigenetics for the past decade and he completed and became an assistant professor at Baylor College of Medicine in 2015. And he also has his PhD in the epigenetic regulation of host immunity. I am telling you he is the expert on immunity and all things epigenetics. I hope you enjoy. And now for my guest, dr Andrew DiNardo. Welcome to the Everything Epigenetics Podcast. Dr DiNardo, I appreciate you being here today.

Speaker 2: 2:06

It's my pleasure to be here with you.

Speaker 1: 2:09

Yeah, so I'd love to hear a little bit more about your background and how you ended up where you are today, and we'll talk about things that you're studying currently, in kind of the next question. But can you just talk about, yeah, your journey? I'd love to learn a little bit more about your background.

Speaker 2: 2:27

My journey. Sure, I did an internal medicine residency and I knew I was interested in global health and tuberculosis and I was falling in love with the immunology of tuberculosis and, interestingly, there has been a lot of work on helminth and tuberculosis co-infection, showing that helminths increase the risk for tuberculosis. And outside of the United States there's a large population that's affected by both helminths and tuberculosis. And I'm also married to an oncologist and I remember one night going to bed and my wife was showing me what she was working on and it was IDH inhibitors and these IDH mutations that they found in leukemia and glioblastoma that lead to epigenetic changes and then lead either to glioblastoma or leukemia. And she was walking me through this and I had just read a paper by Indy Malhotra from Kenya, a really interesting paper. They were looking at the BCG-induced vaccine response in children that never had schistosomiasis but when they were in utero their moms had schistosomiasis and the kids born to moms who had schistosomiasis had a 26-fold lower BCG-induced interferon gamma response compared to the kids who were born to moms that didn't have schistosomiasis.

Speaker 2: 4:12

And I just put these two things together my wife's work that she was explaining to me on epigenetic changes in leukemia and I said, hey, I really want to study this. I want to see if helminths result in epigenetic changes that are predisposing people to having an increased risk of tuberculosis. And eventually that led me to my first major studies. I finished my infectious disease fellowship. This is what I worked on during my infectious disease fellowship and it's been what I've been working on now for about the past 10 years.

Speaker 1: 4:48

Yeah, yeah, no, thanks for that background. That's super fascinating, especially you said you know the story of you and your wife kind of you were looking at some of the work that she's doing. I think that's always interesting seeing you kind of you know both take a lead in the field. So, yeah, you're an infectious disease specialist investigating immunology of co-infection, tuberculosis, epigenetic regulation of immunity, HIV and global health, just to name a few that I pulled off of your website there. Can you talk a little bit more just about the current work you're doing and what you're studying? We'll get into some of the specifics and the papers that you published here soon. But yeah, you know what are you most excited on or looking at studying currently?

Speaker 2: 5:34

Well, we're looking forwards and backwards a little bit is one way to explain it. So in terms of looking forwards, we're looking at children and adolescents. Forwards, we're looking at children and adolescents. We did a school-based deworming program. So in Eswatini we went to different schools and every other year they're supposed to get dewormed, based off of international and national guidelines. And what we did is we added to this a randomized control trial of revaccinating them.

Speaker 2: 6:07

So the standard TB vaccine is given at birth and it works great and not so great. So the standard TB vaccine, bcg, prevents disseminated tuberculosis in kids but loses its effect and doesn't really protect against pulmonary tuberculosis in adults. So the question we wanted to ask here was do these kids who have schistosomiasis and we already know that kids with schistosomiasis lose their BCG vaccine immunity they also lose hepatitis vaccine immunity almost any vaccine that's been studied. So these asymptomatic Helminth infections, they're asymptomatic but they're ruining vaccine efficacy. So we just finished that study. We're just getting started now on the analysis and looking at the immune response to see were we able to revitalize the immune response in these kids and what was the epigenetic landscape of the kids who did develop an improved vaccine immune response versus those who didn't develop an improved vaccine immune response versus those who didn't. So I'm quite excited. That'll probably be at least a year of analysis and staring at a computer to get to the bottom of that. So that's kind of thinking about how we're going forward, looking at how one infection leads to DNA hypermethylation changes and affecting the immune response.

Speaker 2: 7:47

In terms of looking backwards, one of our other findings and now it doesn't seem that unexpected, but at the time I think it was a little bit was that even after successful therapy for tuberculosis, the epigenetic landscape doesn't go back to normal. And we've seen this. You know, if you look at the most common mouse model for this is chronic LCMV infection. So once you have a chronic LCMV infection in the mice, the epigenetic landscape stays perturbed for a very long time. Epigenetic landscape stays perturbed for a very long time.

Speaker 2: 8:31

So our previous paper showed that the same thing happened with individuals who are successfully treated for tuberculosis. So now the big question is so what? What's the clinical impact? Well, we know that individuals who have tuberculosis, even after successful therapy and it's the same thing for COVID, it's the same thing for severe and it's the same thing for COVID, it's the same thing for severe pneumonia, it's the same thing for sepsis and there's a longstanding history I think Charles von Perquette was one of the first people that identified this in 1907, that kids with measles never recovered their TB immune response and were increased risk of TB. Well, individuals with tuberculosis their inflammatory state doesn't go back to normal, so they're increased risk of cardiovascular disease. They're increased risk of cancer. They have recurrent infections. So the other big thing we're working on right now is following people after so-called therapy to look at which are the DNA methylation changes associated with a bad cardiovascular event afterwards and hopefully that can help shed some light on the pathophysiology and hopefully from there we can find some ways to mitigate that risk.

Speaker 1: 9:49

Yeah, definitely I'll be excited to follow along that study and I liked how you mentioned it. You know kind of in the future and you know the history of everything you've done so far, we'll be able to compound and learn more and more on this. I think you're absolutely right. The next question and one of the questions I always get day to day from mostly these healthcare providers that I'm working with is hey, what's the clinical use, right? How can I make this clinically applicable? So we're getting there.

Speaker 1: 10:15

Like you said, you're going to have to do some data analysis for the first study. You mentioned sitting in front of a computer for a year or so. We're kind of just with my work getting done with a two-year study and again, most of that was sitting in front of a computer, making sure things are, you know, working correctly, I should say, and processing. So that's great to hear about some of your work, dr DiNardo, and I appreciate those explanations. You know we've been kind of chatting about your main focus being that epigenetic regulation of immunity, which of course is why we're having this conversation today and what I'm most interested in. So you're doing all this great work. What if we push the boundaries a little bit, you know. What else can we really learn about immunity through the lens of epigenetics? I know you talked about some things currently in the clinical impact, but is there anything else you would want to add there?

Speaker 2: 11:10

Wow, I think when this field opened up 10 to 20 years ago, it was a brand new field, I think now I don't think anyone's going to argue that the entire immune response is regulated through epigenetics. It's one of the many ways that host immunity is regulated, but it's a pretty significant one and it seems like every day, especially now with the advent of single cell technology. Single cell technology, you know, we're we're identifying a new subset of immune cells, um, and a subset of a subset of a subset of immune cells, uh, for some of them, for I mean, uh, one of the subsets that we're studying is okay, well, cd8 cells are a subset of of T cells, but but then you have exhausted CD8 T cells. Oh well, hold on a second. Now there's progenitor-exhausted CD8 T-cells, and the progenitor-exhausted CD8 T-cell has an epigenetic landscape that's different from an exhausted CD8 T cells. So you know, technology is allowing us to define these different immune subsets at much higher resolution and clearly our bioinformatic friends are helping us a lot with that.

Speaker 2: 12:41

I think, combining that high resolution, the high resolution that we can do now in the lab, with well-delineated clinical cohorts, to understand the applicability of what we're looking at, I think that's the exciting thing, or one of the most exciting things moving forward for me, which is the immune cell and what's the epigenetic landscape of that specific immune cell that's going to tell me this TB patient only needs two months of therapy and I don't have to worry about cardiovascular disease afterwards. Or this TB patient needs nine months of therapy and they're at really high risk of post TB lung cancer. So you know, and I can be a little jealous here I've seen the cancer field and it's developed into precision medicine and they look at molecular medicine and based on somebody's IDH status and their flip three status, you know they get different therapy. We're not there for infectious diseases yet, certainly not infectious diseases of the global nature that tends to affect people in resource constrained settings. But I think we can get there.

Speaker 1: 14:10

Yeah, yeah. Well, I love you being super hopeful. I think we can get there too. And you're exactly right With the epigenetics and the single cell and all these different immune cell subset types that we're getting into. If you think epigenetics is an entirely new field, I think the immune cells and epigenetics is going to be its own field as well. I think you know the immune cells and epigenetics is going to be its own field as well. I mean, there's just so many things to unfold there. One question I have for you, based on that answer and a lot of your data analyses of looking at epigenetics and these different diseases and outcomes, are you separating out the immune cell subsets in a lot of those and looking at that? Or, you know, can you maybe talk about some of that data analysis? I'm just curious as well.

Speaker 2: 14:49

The short answer is yes and no, and it's not good enough. So, sheesh, it feels so long ago, but it wasn't I mean. So the schistosomiasis paper that I had mentioned earlier we had isolated CD4, so from peripheral blood mononuclear cells, so from the immune cells circulating in somebody's blood. We isolated CD4 T cells and then we implemented DNA methylation analysis using an alumina-based sequencing method called the DNA methyl epic array, but then also using MSREqPCR, where you digest the DNA with enzymes that can only digest under certain DNA methylation conditions and running PCR. So we validated it in two different ways and I was super proud of the work that we did, and I remember presenting it a few months later and they said but you didn't control for the different CD4 subsets? I said, yep, we did it.

Speaker 2: 15:54

And so then the next paper was on tuberculosis, and in this case we actually used an in silico approach where we took all of the PBMCs and ran the DNA methyl epic array and then used a bioinformatic in silico approach to identify CD8, cd4, cd14, and CD56 DNA methylation status for each one of those cell types. And then again we were discussing it and that was still a pretty major advance at the time and someone said ah, but you didn't account for the different subsets of each of those. So now we're doing single cell technology, and with single cell technology, I mean this is a bit of a curse because, yeah, you can. Hey, I found a subset of two cells. What the heck is a subset of only two cells cells?

Speaker 2: 16:47

So we have to be careful at what resolution we now look at things and we're in um a place that that, uh, we're going to get pushed off a cliff if we're not careful with our bioinformaticians. Um, and then and then this comes up well, is all of the premature epigenetic aging stuff that you do? Um, is that really just seeing a loss of naive cells and a progression towards exhausted cells and more developed cells? And there are experts I hope there are some experts listening to this that will know how to answer it better than me. But it's something we're going to have to work on and we're going to have to try and explain better in the future.

Speaker 1: 17:33

Yeah, I think so as well. Yeah, you know there's a lot of thought and effort that goes into these pre-processing steps and kind of taking out those immune cell subsets and stratifying, and it seems like with your work you're very well aware of that and you know you're doing that, but then people are asking you to dig deeper and deeper and deeper. So you're picking away at this and I'm excited to see what you find out there and hopefully we'll get an answer on that as well. The last question you kind of pondered on there I want to take into one of the specific papers that you've published. It's it's titled the the post infectious epigenetic immune modifications a double edged sword. Um, you know, I I really liked the title of this, this uh paper, and I want to dive into that statement a little bit better. Can you, can you maybe describe what you did there, what you wrote and what you mean by the double edged sword?

Speaker 2: 18:25

Sure, um, so the term the double edged sword was was uh, was? Dan Musher, one of the co-authors, suggested that, and I guess the whole manuscript really started with him. In 2017, at our local journal club, I presented a cutting-edge paper from Mihai Natia's group. From Mihai Natia's group, rob Arts was the first author and they showed that innate training was not only epigenetically mediated, but it was mediated specifically by the Krebs cycle, and changes that happened in the Krebs cycle were inducing changes in epigenetic landscape that were leading to innate training. I was so proud of presenting a very complicated manuscript to Journal Club and Dan Musher, who is currently 82 years old, waved away my explanation and said we've known this for 40 years. He said, dr Musher, we didn't know about epigenetics 40 years ago. What are you talking about? And he walked me through some old studies by George McInnes, some other studies from the 1960s and 1970s that showed the phenomenon that we didn't know the epigenetic mechanisms, but we knew the phenomenon that non-lymphocytes and lymphocytes had a different response to a second pathogen after an exposure to a first pathogen or something similar. So that manuscript, then, was a way to try and explain and link the historical context that we've known for at least 100 years. Some of the studies back to the 1890s and early 1900s, link them to modern epigenetic mechanisms, and so the first half of the manuscript was okay. If you have a monocyte that sees BCG or beta-glucan, it then has a better immune response a couple months later if it sees a different pathogen and a lot of live attenuated vaccines have this effect, and during COVID a lot of people were looking to see. Well, until a COVID-specific vaccine comes out, what can we do to improve innate immunity in order to fight COVID? Well, the second half of the manuscript was the dark side.

Speaker 2: 20:57

If you have a severe pneumonia, if you have tuberculosis, if you have severe sepsis, if you have severe COVID, there are long-lasting detrimental effects that we've discussed. Increased rate of cardiovascular disease after COVID is very high. Increased rate of all-cause mortality after you survive sepsis is more than twofold higher than propensity match controls For tuberculosis. After surviving tuberculosis and after so-called successful therapy, you have a 3.7-fold increased risk of death compared to age and propensity match controls. And there are detrimental epigenetic changes that occur after each one of those severe infections. So the double-edged sword is there are epigenetic changes that regulate a beneficial immune response after a mild immune exposure, such as after BCG or after immune cells are exposed to beta-glucan, and then the opposite occurs after a severe infection, and the point of that article was to discuss how we might be able to manipulate that in the future as part of improved care.

Speaker 1: 22:22

Yeah, that was my leading question. Okay, so you have these. You know parts that are pulling away from each other. Do they cancel each other out, do they compound? You know how does that kind of look as a result? So I thought that was an interesting find in your work there. So, yeah, I wanted you to elaborate on that further. Another paper I saw of yours. I was really excited about this one. We've again been chatting about all these things kind of throughout our conversation here. You have a paper titled Increased DNA Methylation, cellular Senescence and Premature Epigenetic Aging in Guinea Pigs and Humans with Tuberculosis. So yeah, can you go ahead and describe this one, dr DiNardo?

Speaker 2: 23:04

This was a super fun one. So before the pandemic, when we were still having fun in person meetings, I went to a tuberculosis conference and there were two of us that were presenting posters on DNA methylation and I was presenting my work that TB patients had DNA hypermethylation and the negative effect that had on the IL-12 interferon gamma pathway. Well across the poster aisle from me was Carly Boback from Dartmouth who had done this beautiful work data mining, publicly available transcriptomic data and her conclusion was TB is going to affect DNA methylation. And I was like, yeah, look, it does. And we got the joke about that and we started talking about how we could understand this better. And a brilliant postdoc in my group, dr Abhimanyu, worked with Carly to data mine a little bit more. And there were some previous papers about oxidative stress and cellular senescence and we hypothesized that they would correlate with DNA hypermethylation. And they did they very strongly correlated with DNA hypermethylation. And they did they very strongly correlated. And so then we pulled in Jeff Surio from Texas A&M to help us with the guinea pig studies. So we have a nice paper that shows an association and a correlation between those different phenomena. So that leads the question of well, can we manipulate one of those.

Speaker 2: 24:51

So initially, when we found the DNA hypermethylation in tuberculosis, I said okay, well, if you have DNA hypermethylation of these critical immune genes, can we use hypomethylating drugs to reverse the DNA hypermethylation? And that seemed like an obvious next step. Well, the problem is most DNA hypermethylation, dna hypomethylating drugs. They're used for one thing, and one thing only right now, which is chemotherapy for people with myelodysplastic syndrome and leukemia. We don't know how targeted they are, we don't know what they're, they're really not studied in people who aren't extremely sick with cancers. So we were unclear about their safety profile and they're actually quite hard to work with in in vitro systems.

Speaker 2: 25:44

And there were enough studies that had come out that showed, as I mentioned previously, that intracellular metabolism is directly leading to epigenetic changes. So we came up and we put a position paper out a few years ago at least three different metabolic epigenetic rheostats that we identified and we started testing. Could we manipulate the intracellular metabolism? So that's what we've been studying in vitro and we've got very exciting findings there that we're trying to make public. If you try and improve redox homeostasis, if you try and slow down the TCA cycle from going into overdrive, because when the immune system is activated, the so-called Warburg effect occurs and the TCA cycle ramps up, and what we can see, from in vitro studies at least, is that that is driving a lot of the DNA hypermethylation changes.

Speaker 1: 26:55

Sure, yeah, very, very interesting and and pretty cool is how. How then you said you met Carly from that, that conference, right, and that's how kind of the paper started. Was that correct?

Speaker 2: 27:07

Yeah, that's pretty neat. There's the advantage. I complained about the pandemic. The advantage about the pandemic is we're all very capable of interacting from long distance. So we met on Zoom on a regular basis and Carly's really did some fantastic work for that and I know she's still doing a lot of very nice TV work and I hope to see her more on Zoom.

Speaker 1: 27:36

Yeah, that's great. I always love how papers start and hearing those stories, and as you ask more questions, things start to unfold, so you get some really interesting background that no one really knows about. So I thought that I wanted to kind of ask that there.

Speaker 2: 27:49

The advantage of going to in-person meetings and sitting at the coffee station, sitting at the cold drink station and just chatting and talking turns into really good science.

Speaker 1: 28:02

Absolutely Not a doubt in my mind with that. So no, that's a really interesting paper you have there. And I know when I had you fill out my little podcast guest sheet I don't know if you remember it was a while back, but you also kind of entered a topic you may have wanted to go over. So mTOR right, does that have anything to do with this study? And I actually haven't talked about mTOR at all with anyone on the podcast so far. So if you could give our listeners an introduction to that, I think that would be a really good place to start.

Speaker 2: 28:32

Oh man, there's so many good introductions to mTOR. That's such a responsibility. Well, what I would probably say is listen, I think it was the Daily's podcast on mTOR. But mTOR mammalian target of rapamycin and what's so much fun here is there's so much history behind this target, how it was discovered, the lab that discovered it and everything that happened. Um, uh, so they discovered this.

Speaker 2: 29:06

They oh so um rapa nui island in one of the easter islands and, and um, it's as an immune I hate to say immune suppressive drug.

Speaker 2: 29:19

It's an immune, um modulating drug.

Speaker 2: 29:22

It maybe is a better terminology, uh, but it controls intracellular metabolism.

Speaker 2: 29:28

So, as I mentioned earlier, when immune cells are stimulated, in order for the immune cells to do their effector function and for them to proliferate, they need a lot of intracellular intermediate metabolites, and the TCA cycle acts as a hub for these critical metabolites that have to be produced to replicate your DNA and proliferate, to do all the effector functions that immune cells need.

Speaker 2: 30:00

So mTOR is one of the critical metabolites, proteins that regulates metabolism and, yeah, so it's been studied a lot with the immune system and I believe John Wary's group has a nice article from a few years ago showing that mTOR inhibitors can prevent T-cell immune exhaustion in an LCMV model. There's a lot of new studies on using mTOR inhibitors for tuberculosis and that's why I hate to call them immune suppressive drugs, because they seem to both decrease inflammation but improve immune responsiveness. So while they improve, decrease basal inflammation, they allow the immune system to respond when activated again in the future, and we've been studying how they affect DNA methylation landscape in the setting of immune exhaustion and immune tolerance in vitro models, with the hope that if we slowed down the TCA cycle, that slowing down of the TCA cycle would lead to less DNA hypermethylation in the setting of a severe or chronic infection.

Speaker 1: 31:23

Yeah, that makes sense. No, thank you, I think you did a wonderful job and I can put some of the assets that you noted and link those out in case anyone wants to learn a little bit more. But I think mTOR, rapamycin and rapamune these are all buzzwords in the space right now. People really want to know how rapamycin is affecting a lot of the epigenetic biological age clocks and I don't think we exactly know yet. There are still a lot of questions about that.

Speaker 1: 31:50

There is the Pearl trial, I believe it's called, where they're trying to, you know, use rapamycin from an interventional standpoint, you know, for anti-aging purposes, and see how it affects the clock. So hopefully more to come with that trial soon, but I don't think it's, I think it's still ongoing. So, so, so yeah, dr DiNardo, uh, focusing more on on on your work and everything that that we've been discussing, um, what about the, the applications? Uh, can you tell me? Uh, you know, is anything close to commercialization, to more of that clinical use? What else can we, we know about all the wonderful work that you're doing?

Speaker 2: 32:33

Commercialization In terms of a signature. No, the cohorts in infectious diseases sometimes feel embarrassingly small. Sometimes feel embarrassingly small. So if you think of the, are you familiar with the TCGA, the Cancer Genome Atlas? Nice pun on words with using TCGA, but it's thousands of cancer patients with transcriptomics, with epigenomics, proteomics and clinical follow-up.

Speaker 1: 33:09

Yeah, I'm not familiar actually.

Speaker 2: 33:12

Yeah, so it has revolutionized every single type of cancer. So you name a cancer out there. And the TCGA is one of modern medicine's greatest achievements. It has. There's probably five New England journals just on breast cancer. By making this giant repository of all of this data, so many papers now start off by saying, hey, we data, mined this public data, we found this signal, we tested it in this model. Look, we found a new drug. Hey, we tried this new drug on patients and hey, this new drug actually works on this subset of breast cancer or this subset of leukemia.

Speaker 2: 33:59

We don't have anything like that for infectious diseases. Show me an equivalency for bacterial pneumonia, show me an equivalency for sepsis, for tuberculosis, for any of the major infections. There is no single organizing repository. So if you ask me my wishes, one because I could use it, but I think you know anybody with a computer and access would be able to make use of a similar atlas for infectious diseases. So if we know infectious diseases are one of the things that leads to increased morbidity and mortality, outside of the problem of infectious diseases, because it increases cardiovascular disease, because it induces premature aging, because it increases the risk for cancers, this could be a major project to improve there and help identify what are the signatures that we need, what are the epigenetic signatures that we need to be able to identify to prevent those things and then to learn from them. So that's probably one of the things I'm most excited about.

Speaker 2: 35:08

The other one, as I mentioned earlier, is our findings that we might be able to manipulate metabolism to improve the immune response and improve epigenetics. My colleagues have been teasing me recently because every single presentation I give ends up with me saying eat your vegetables. But we've been studying lycopene, we've been studying carotenoids, and different carotenoids really seem to be quite impressive in their ability to prevent some of the epigenetic scars that we're seeing in in vitro models. So if you asked me, you know you can only do one study, one interventional study, over the next five years. It would be using these really cool new devices that are cutaneous spectrometers that you know you can just flash on the palm of your hand and it can tell you if you have enough carotenoids in your body. I would love to apply that to a post-infectious model and say, hey, you're not eating enough vegetables. I can tell you right here, based on the pigment I can detect on your hand, and see if we can actually intervene right there.

Speaker 1: 36:31

Wow, yeah, super interesting. I don't want to know. I know I need to eat more veggies, but I think that's a good application right For someone. And you have to tell us now, dr Jarno, if you had to pick one vegetable that we had to eat, or carotenoid which one would you say I don't know, according to the data, or what you think we should do. What'd you say According, I don't?

Speaker 2: 36:50

know according to the data, or what you think we should do. Unfair, unfair. But I'm going to have to go with my Japanese postdoc who has introduced all of us. I'm going to cheat, I'm going to say seaweed, because it's not one vegetable, it's hundreds of vegetables. But our, our, our Japanese postdoc has introduced our team to the benefits of seaweed and I know some people just don't have the taste for that. But whatever you like, I mean we joked. We started with lycopene in the lab, because I have Italian origin. We've looked at many different ones. I mean alpha and beta carotenoids look fantastic. So we get a lot of carrots passed around. I don't think there's a single one. But if you had to make me choose, seaweed looks pretty amazing.

Speaker 1: 37:41

Interesting. Yeah, no, I currently don't have seaweed in my diet whatsoever, so I'm going to maybe look up some recipes after this or see how you know how you can can eat it and try to incorporate that more. Um, no, that's great. That's great. I'm excited for you, for your work that's coming out the the applications. I think I I've said this multiple times as you know researchers and and we we need to be collaborative. We need to create these kinds of these, these minds of of of data, these, these repertoires, so people can come and we can learn new, new insights. So I'm excited to see your work there and hopefully put together some type of database, just like you said for for the cancer one.

Speaker 1: 38:19

You led me perfectly into my next question for you, basically just being. You know, you also mentioned there's there's a lack of data in, in, in the infectious and induced premature aging, what we were just mentioning. What about other limitations in this field? Is there anything? If you said, hey, if I had this one thing or if I could choose something, then my work would be a lot easier? Any other limitations?

Speaker 2: 38:43

I think what we just discussed, I think in infectious disease research we just have a shortcoming of publicly available data compared to other fields and um, so so I think building that out, um would probably be my number one and I I'm really lucky to have uh christianwarfa as a bioinformatic partner with all of this work, and I think hand in hand with that goes that we need clinicians and clinical investigators and wet lab investigators that can work hand in hand with bioinformaticians. Aai, american Association of Immunology, has a fellowship every year that they call the Intersect Fellowship, just to do this, because they recognize how critical it is that we bring those two fields together and I think that's one of the things that can exponentially help us identify new findings. What has happened with big data over the past decade and a half is truly amazing.

Speaker 1: 40:05

Yeah, I couldn't agree more Again. I always say this too, but if I'm going to say it again, if I could go back into something, because I just have a general science background, I would definitely do bioinformatics, computer science, computer training. I have no coding experience, but when I get a free second or I have a free weekend or something, I'm going to spend time messing with ChatGPT or taking some of those free classes where I mean you know you can learn from those tools now which make them easy, accessible and free right For for the most part. So you know, hopefully I'll increase my skillset with with those here soon.

Speaker 2: 40:39

A hundred percent yeah.

Speaker 1: 40:41

Yeah, well, you know we're almost coming to the end of this, this podcast here. I know you mentioned you were excited about kind of the device and scanning with the different you know kind of carotenoid levels and if you need to eat more vegetable by looking on the pigment of the skin. What else are you excited about and anything coming up next? I know you have so many different you know studies and things you're looking at, but anything else you want to add there?

Speaker 2: 41:09

Those are the critical ones. I'm excited to see the field. There's a lot of metformin studies um in the infectious disease field there's uh um Harvey Kornfeld is running a really nice metformin study on TB. Uh, bob Wallace has a couple um that I'm really excited to see come out. So I think the intersection between metabolism and epigenetics has a chance to push us forward, and what's really nice is maybe it even has a chance to push us forward with food rather than drugs. So those are the things I'm eager to see in the coming years.

Speaker 1: 41:57

Yeah, yeah, I like that as well. Right, you always hear, like food is medicine, right, things like cliche sayings like that. So it definitely has truth behind it. All right, the last question I usually ask it's a curve ball has nothing to do with your work, but, dr DiNardo, if you could be any animal in the world, what would you be and why?

Speaker 2: 42:18

I have always wanted to fly, so I think I would have to go with either a screech owl because they're so cute, or a peregrine falcon, because they're so fast. One of those. I love it. You knew it. You knew the answer. Oh, either a screech owl because they're so cute, or a peregrine falcon, because they're so fast. One of those.

Speaker 1: 42:31

I love it. You knew it. You knew the answer and, yeah, I would be curious to learn, to learn how to fly a little bit as well, but I don't think anyone has ever said an owl. So that's yeah, that's really unique. I like it.

Speaker 2: 42:46

Here in Michigan we have really cute screech owls. They, they look like um, uh, they, they. You know they're only like six, six inches and they look like little teddy bears and so you go out at night and you can you can catch them pretty well.

Speaker 1: 43:01

Oh cool, yeah, I didn't know that little little fun fact out of there as well. Well, um, again, appreciate all all you've uh taught us here on this podcast today. We're, you know, coming to the end For listeners who want to connect with you or learn a little bit more. You know I'll link everything. But yeah, are you active on, you know, twitter or where can people find and learn more about your work?

Speaker 2: 43:22

I am not active on Twitter. I'm so sorry.

Speaker 1: 43:26

That's okay.

Speaker 2: 43:28

Maybe my boss is right when she tells me I should be um, but I have tried to um be active in my analysis and not so active in um in twitter, uh, email, um, reach out to me by email. I'd love to chat um. I'd love to meet in person at meetings and discuss more. It really has led to some great collaborations. But throw my email in the meeting notes.

Speaker 1: 43:58

Perfect Will do, and I think that's totally okay. You're not on Twitter and more into your analysis and doing that work. I think that's it, of course people are most interested in. So, yeah, thanks again everyone for listening to Everything Epigenetics Podcast. Remember you have control over your epigenetics, so tune in next time to learn more. Thanks, dr DiNardo.

Speaker 2: 44:17

Absolutely my pleasure. Thanks for having me.