Keith H. Baratz, M.D., is an ophthalmologist who specializes in cornea and complex anterior segment conditions at Mayo Clinic in Minnesota. Dr. Baratz joins our podcast to share the fascinating science behind Fuchs' dystrophy and lessons learned over the course of his career.
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Welcome to the Mayo Clinic Ophthalmology podcast brought to you by Mayo Clinic. I'm your host, Doctor Andrea Tooley and I'm Doctor Eric Botham. We're here to bring you the latest and greatest in ophthalmology medicine. And more in today's episode, we sit down with Doctor Keith Barrett's cornea specialist at Mayo Clinic. Doctor Barretts is known nationally and internationally for his work on the genetic and molecular markers of Fuchs endothelial corneal dystrophy. Today, Dr Barrett takes us through his work on Fuchs and how his research translates into clinical care, novel therapeutics and new approaches for surgery, even for the comprehensive ophthalmologist. Doctor Keith Barretts is a professor of ophthalmology and a corneal specialist here at the Mayo Clinic. Doctor Barretts has served on the board of directors for the American Board of Ophthalmology as well as the editorial board for G A Ophthalmology and more. He is a past recipient of the A AO achievement award. Doctor Barrett's Clinical Practice focuses on the medical and surgical treatment of cornea and external diseases, corneal transplantation and cataract surgery. He has a, he has a specific interest in Fuchs, corneal dystrophy and genetic causes and biochemical mechanisms of this disease. Welcome, Doctor Barretts. Well, thanks, great to be here to talk about my favorite topic because how, tell us about that. How did you start to get interest in Fuchs, endothelial corneal dystrophy? Well, we have a lot of folks here in Minnesota, a mayo clinic. So I've always taken care of lots of patients with, with the condition. However, it all really started with a knock on the door. Um, and this was about 2006, 2006. I was doing research some epidemiology, some, some clinical things, but I really didn't have a genetic focus. Actually, not even a genetic interest. I realize I was one of those people who, who knew, you know, basics about, you know, homozygous, homozygous versus heterozygos, not much more and actually got a knock on the door by Al Edwards who was a former research colleague here and he's a brilliant, brilliant fella with a lot of foresight and he knock and Dora says Keith, uh is there a corny condition that we should look into genetics? And it's like the answer is Fuchs. Now, there's already another multi center trial getting started to look at the, the genetics of Fuchs. And I thought, well, and there's this other study, why, you know, why should we embark on it? But Al al said he thought it was doable and the, the goal was to, to work towards a go which is a genome wide association study. And a GWAS typically relies on thousands of patients uh to, to compare 22 groups. So GWS are usually really large studies and just to step back with the G OS is it's, it's, you're looking at the normal variation in nucleotides across the entire genome across all your chromosomes. And large G OS studies now are, are looking at hundreds of thousands to a million different loci in the gene and, and typing the variations. And what you're doing is you're comparing two groups of patients, the control group and the group with the disease and statistically separating them and identifying points in the genome where those two groups are most dissimilar. So it's a way of just pinpointing towards a locus in gene. It doesn't identify genetic defect, it doesn't identify exactly where, where the, the defect or mutation may be, but it tells you where in the gene, those two groups are most dissimilar and al looked at Fuchs. He said this is really a gene or a disease that we should be able to pinpoint just one or two or a couple of genes. GWS are really good for complex genetic traits like myopia. There may be, who knows how many genes but lots of genes that all contribute, glaucoma, lots of genes may be contributing uh Kois and, and many other things such as, you know, just your, your, your, your, your, you know, your mentality, your personality, you know, all these things are probably genetic causes very, very complex and environmental factors as well. Uh But I, I thought that there, we should be able to find just a couple of genes uh for Fuchs because of the, the nature of the condition and garnering wasn't right. We, we recruited a total of about 230 patients in the FS, which is a very small study and we got a very, very strong hit at the transcription factor for gene. So I love stories about serendipitous moments in medicine. And I feel like we all have those things in our career where we've been led different places or a research door has been opened or a project that you didn't even think about. But you alluded to the fact that you had already kind of thought there was a genetic basis. You said you see a lot of Fuchs patients in Minnesota. So do you think it's because there's a, there's a population based uh incidence of higher in kind of Minnesotans are kind of Norwegian patient population or you've seen it in families or what were you, did? You have an inkling before? Well, a couple things, number one, there was a large family study by Jay Kratch in the 19 seventies and he looked at 64 families, he was practicing the University of Iowa. So not, not, not far from here and he, he described Fuchs as clearly being familial. Uh despite his, his study, there were not lots and lots of follow up studies, looking at the inheritance patterns. Uh We still thought there was, there was uh uh spontaneous Fuchs. So Fuchs dystrophy where neither, neither family, neither parent had, had the condition or had a genetic defect, uh which I personally think would, is probably extremely rare. There really wasn't much looking at the genetics and looking at the inheritance patterns for many, many years, but I don't have a reason why it just didn't. Uh but here in Minnesota, because we have a, you know, very strong Scandinavian population, uh we really had the opportunity to study these patients and the fu is most common in Scandinavia becomes less common as you go further south in Europe. If you look at Asia, India, Africa, China, it's much less common there. So we really have the opportunity to study a lot of patients because of the demographics of, of Minnesota, the right place right time was meant for you in your career. So that your study published in the New England Journal of Medicine at some 0.2010 or, and that was the outcome of this serendipity event that looked at the genetic correlations. What, how has that changed your career? And New England journal, it's a landmark piece. How has that changed when you look back over the last 10 years about your ongoing research investigations? Because obviously that was one study, but tell us then how that's changed your, your, your management and care or just perspective on this disease, there are a lot of different levels to, to look at when you answer that question, one is on the research level because that study got a lot of interest from other people and all of some people start looking at that gene. So, so it, it changed the focus. What does that gene do? Uh how might it be causing f So it really started a completely new avenue of research uh here in, in, in other other countries as well as the U on a personal level, had it helped to find my research career. But I also felt like Charlatan because I was publishing an article on genetics. I knew very little about it. So everything in that, in that article uh that the parts that I wrote, I had to teach myself the science behind it and Al Edwards of course, you know, contributed. So, so he, he, he did the heavy lifting on that article. Um It's also taught me to have humility for what you're doing. Uh because I really started from uh a point of very little knowledge and had to teach myself and looking back at how little I knew when we were in the middle of doing this research and publishing really made me, makes me humble. Uh And even now, I, I think I should be very humble, my amount of knowledge on this, in this field and the genetics is still very small compared to what we'll know in five years or 10 years. So it's really taught me humility as a researcher. You know, we, we sit here in an academic institution celebrating the lifelong learning. We all get to have as we research and teach and research and teach and continue to advance a field. And part of being in academic medicine is that humility over there's a lot, I don't know and there's a lot I want to know. But I think your example is wonderful on how this is an area that you in your career found an opportunity and expanded your knowledge and the more you learn, the more you realize, I don't know. Um I would say for all of us, I think genetics is just this new frontier that keeps all of us humble and this changing paradigms in terms of our, you know, our, our phenotypes of what we see in the clinic. But what a wonderful thing it is that you've testified how you, you saw this opportunity, you dove into it and how it just with time and onward hunger and, and investigation, you've become an expert in this niche. Exactly. And also I surrounded myself with people who are better than I am in the areas that I have less knowledge. Uh The Al Edwards was no longer in Mayo. So he got started on this project. But after he left Mayo, I was, I had a Agwatag was data. I had a gene. But what do you do with that? So I just knocked on a couple of doors and I knocked on the right door, which is Eric Ween, who is one of the senior individuals in our, in our genomics area. And he looked at my paper and it took a couple of knocks on the door to get him to, to get his attention the first time. Uh, I didn't get his full attention, but eventually I met with him, put the paper on his desk and, and that, that got his attention. He went home for the weekend and he came back and said, there's a genetic defect in TCF four looking for a disease. So there's something going on in this gene. It should be cause causing a disease. It should be pathogenic, but there's no associated disease with it. And that's the repeat expansion in the transcription factor for a gene repeat expansions when you have nucleotides that repeat abnormally. And in Fuchs, it's AC TG trinucleotide repeat. And this, it's actually Ron. So it's not in part of the gene that codes for a protein. It's an Ron, which is non coding part of the gene. But the CTG repeat in nor most patients, they'll have a dozen, 2030 repeats. But in fu there are at least 50 or 60 in the blood, but there may be thousands of these repeats in, in the cornea. And the interesting thing is, it's not a static mutation. This mutation can change over time within the cell. And the reason for that is too, too complex to go into right now. But we may measure repeats in white blood cells of 70 80 100 and there may be 3000 of the CTG repeats in the cornea. So, how common is that in genetics? I, I don't think I was quite aware that different parts of your body would show a different number of repeats leading to different disease states depending on the tissue with, with repeat expansion expansion disease. It is uh and repeat expansions are unstable mutations. So your, your DNA can, can shorten or lengthen as uh as time goes on. So even in a cell cell, a non dividing cell like the brain like coronelli, that repeat expansion actually lengthen. Uh There's a whole set of, of DNA repair mechanisms continually going on to, to repair your DNA during your life. And these long repeat expansions tend to gum up the system in lots of ways, lots of ways. And one of those ways is it can allow the, the repeat to, to lengthen. We don't have exact, we don't have any knowledge of why the cornea uh as opposed to other other parts of the body. Uh why is the cornea the only thing that's affected in Fuchs, dystrophy as far as we know, and I want to underline it as far as we know. Uh And, and that's a great, you know, a great, great question to ask. And that's something we're looking into. We do know uh some things can happen with other repeat expansion diseases. The one that most closely mirrors fu dystrophy is myotonic dystrophy type one. It's a similar CTG repeat expansion. Uh It's in a, it's not in the a a coding portion of, of the gene. Uh And also with that condition, there are differences in the expansion length in the brain as opposed to white blood cells or or elsewhere, but a lot of similar similarities. But between the two, the two conditions, Huntington disease is another repeat expansion disease, uh spinal cerebral or taxes some of those. And the next one is uh a repeat associated form of A LS. Ok. So I I'm curious on how your research has translated then over to your clinical practice, you know, what types of novel therapies or approaches or, or has there been, has it made you look into or be curious about or, or consider to help an individual patient? Well, of course, the ultimate goal for the research is to come up with a cure or at least come up with something that, that prevents the disease from progressing. There's a lot of interest now in, in the research community in bio pharma. Uh there are some clinical studies that are going on now, others are being planned, a lot of medications in the in the pipeline to actually target this genetic defect to either splice it out and edit it using CRISPR like techniques or to silence the gene using a variety of other techniques. So, as far as is the disease, I can't say there's really anything in the clinic yet, but we may not be far off. However, because of, of my interest, I've seen all these patients with FU. So, so, you know, we, we just over the years, um I've seen thousands, really thousands and we have blood samples on thousands, we have tissue samples on, on hundreds and hundreds. So I really, really just paid a lot of attention to what I see. And one of the things that we've been working on, I have Sanjay Patel really to uh uh yes, he's done really, the most of the work on that is imaging, imaging, using shine flu photography, shine flug imaging. And that's become an important part of the clinical evaluation. At least the mayo uh in how we evaluate these patients. Uh other treatment. I can't say our research has directly led to other treatments, although I'm confident that that it will. Uh but there are definitely other things that, that are coming down the pipeline, other um really, really interesting surgical techniques, uh eye banking techniques. You know, if I look back at my career, uh there's almost nothing I'm doing now that I was doing 30 years ago. And according to transplantation is, is one of those things, you know, right now for Fuchs dystrophy, the gold standard, at least I believe the gold standard is decimate membrane and iffier plasty. Uh Other people are also uh looking at uh decimate membrane stripping with al chop plasty just allowing the peripheral endit to repopulate. Uh But these surgical techniques are light years from what we're doing 20 years ago with penetrating chop plasty. It's a quicker procedure, it's less risk. The patient gets better vision, uh quicker healing. And now we're doing surgery, you know, sometimes just a few weeks or couple of months apart, which we'd never have thought of doing when patients had panic chop plasty or dealing with sutures. And you know, a million doctors of astigmatism, we just don't see those issues anymore. But I think the future the transplantation may be cell based right now. Uh one donor, one patient. And the challenge is there are people all over the world who need corneas and can't, cannot access them. There's a very well known article, highly quoted article that, that calculated that only one out of 70 patients worldwide who needs a cornea transplant can actually access it. And most of those of those are underdeveloped countries. Most of those patients who need, who need penetrating chop plasty, they just can't access it and looking at the really big picture of what we're doing. Now, if we could culture endothelial cells for transplantation and take one donor and potentially turn it into enough cultured tissue cultured cells for 100 donors, then that would free up 99 other corneas that we could send overseas. So I think looking at the really big picture is the future of corneal transplantation, hopefully will make corneas more readily available worldwide. So what is cell based therapy, cell based therapy is culturing your cornea tissue and culturing the endothelium and injecting those cells into the into the eye. Uh those clinical trials are happening right. Right now, some of this work was developed in, in Japan. Uh some of some great researchers who had some some wonderful ideas on on how to do this. And there there are clinical trials that are taking place right right now. Um and it's fairly well, relatively simple, strip off decimate membrane or maybe not even strip off, decimate membrane, inject some cells and those cells will repopulate the cornea cornea, the end of field. Now, granted these are an early, very early phase studies, but I think that's going to be the future of taking that one step further. How about autologous tissue? How about taking some cells from somewhere else in your body, some stem cells and engineering those cells into corneal endothelial cells and then injecting those cells into your eyes. So it's your own cells. Uh There are a few steps to be to be worked out there. Uh It's an incredibly expensive technology. So you can't simply just take your stem cells and you know, put them through a series of, you know, test tubes or reactions and spin them back into your eye. Uh engineering stem cells is extremely expensive uh process, especially if you're going to do it for patients, if they approved et cetera. Uh but, but the technology, the the basics are there and people are working on this. So it is doable. I think the doors that have been opened from, from all of this, like you said in the past 20 years, it's unbelievable how far it's come. Just looking at fu specifically as a little microcosm of how far we can go in terms of translational research. It's really incredible. I want to ask another kind of big picture question thinking about the comprehensive ophthalmologist, the cataract surgeon. What are your best recommendations for them to manage Fuchs clinically, like talk about some imaging stuff for for evaluating progression and then even with uncomplicated cataract surgery, what should we be thinking about as a comprehensive ophthalmologist? Uh I think there's nothing better than your clinical exam. Uh getting a really good look with high magnification at that endothelial cell layer. I rely very heavily on a slant that has high magnification modes. You know, many of our lambs have two magnification levels and I can't see what I need to see with some of those, those devices I really rely on on high magnification and with high magnification using specular reflection techniques. In most patients, I can see the cells or if they have confluent guta, you don't see the cells. But I really, really rely on my clinical exam to, to determine whether this, when a patient has GTE, whether there's an endothelial reserve. Because if your clinical exam is good enough, you should be able to identify cells between the GTA or if there's nothing but GTA in those cells. So your clinical exam, I'd say if you're going to do a lot of cataract surgery patient of the fu work on that clinical exam. Number one, number two, as I mentioned before, really excited about shine fluid imaging. And again, you know, kudos to, to Sanjay Patel and, and uh the team that he's, he's worked with to bring this technology to, you know, to everyday day clinical use. Uh It does require special imaging. You know, we have a PAC CAM device. Uh but with the PIC CAM device, we're looking for some very specific tomographic features we're looking for uh for thickening of the cornea that has a certain pattern. We're looking at the posterior contour map. We're looking for depression in the central part of the cornea where the central part of the cornea bulges into the interior chamber, right? Because there are other findings, not just central corneal thickness. And that's what that's what I think about when I'm thinking about foods, I think central corneal thickness. But so you there's other findings that are even more specific to predicting progression. Yes, I I think what we're finding is more of a tomographic pattern. And topography is, is basically the thickness and shape and volume of the whole cornea. But it's the, it's a certain pattern rather than just the thickness and a nice study that was done that looked at patients with Fooks going, going ahead and having surgery versus their unaffected, unaffected relatives. And it was really interesting because the amount of overlap between normal patients and patients who have Fuchs as far as central corneal thickness that overlap is huge, is huge. So central corneal thickness alone really doesn't distinguish uh the two groups whatsoever. We'll see patients who have perfectly normal corneas, perfectly healthy with a thickness, uh approaching 700 microns. And I have transplanted patients for folks who have corneal thicknesses, central thicknesses and low five hundreds. So the thickness itself doesn't tell you a whole lot. Yeah, it raises your index of suspicion. Uh but it does not replace your clinical exam. And I don't, I think it pales in comparison to, to shine fluid imaging in the tomographic patterns. When we see that specific tomographic pattern, we also correlate that with a patient who is likely to progress or likely to develop edema after cataract surgery or likely to have symptoms related to, to the cornea. So we see that tomographic pattern that's for us has become kind of that that cut off between when we decide that patient needs a transplant as opposed to can you get away with cataracts surgery alone? That's, that's very helpful because I think the comprehensive ophthalmologist, that's a, that would be a big question, you know, do they need a transplant or can I just do cataract surgery? You imagine what practice was like years ago before we had oct to the macula? I think 10 years from now, we'll say, can you imagine those days before we had shine fluid imaging or another imaging modality to look at the cornea. So I'm curious in the evolution of management of cataracts in the setting of a fu patient. Historically, I remember when I was trained quite a while ago that there was, you use the clinical tools to decide whether you could do a cataract surgery safely and not deal and let the cornea be the cornea disease as it was or whether you needed a triple procedure with a full thickness corneal graft. Now that the corneal transplants have changed and we don't do full thickness graft for Fuchs as much anymore. Has the um decision point in which you do only cataract surgery changed at all. It's, it's a great question. Um I would say the decision point probably has changed. I think the threshold for doing a transplant definitely has changed. Uh In the old days, I gotta be careful how I use the term old days because I was practicing in those old days uh to do a transplant, a full thickness transplant. A patient is 2025 or 20 even 2020 visual acuity with early cortal edema with heresy, you just don't do that. But these days if the patient has tomographic edema or clinical edema, well, imagine the visual acuity chart and high contrast acuity is relatively less important. Uh but also one aspect of that as well. Since transplants are easier to do, now, they um you know, the outcomes are better or surgeons more cavalier operating in these conditions. And I don't, I wouldn't say so. Ok, because it's still pretty uncommon to see patients who have Fuchs and have cataract surgery and have decompensation. Yes, of course, it happens. But I, I, seeing it is a, is an, something's becoming more common. I think the cataract surgeons out there are so good and so facile and take all the steps to protect the, the cornea. Um I don't think that they're being, they're being cavalier because they've got the tools in their toolbox to be really careful and really good surgeons. And I actually, I think it's kind of surprising the patients with f dystrophy, I have cataracts, they can undergo cataract surgery without the cornea getting much worse. I, I would actually think it would be a more common problem and I'm kind of surprised in the situations I see in my patients and other doctors, patients where the cornea looks basically the same after surgeries as it did before. Um, part of that is the resilience of the cornea. But a lot of that is, is our are, are really nice surgical techniques for cataracts surgery. Oh, that's very encouraging. This has been absolutely outstanding. I've learned so much. We will link in the show notes, links to uh several of your papers. Definitely, of course, your New England journal paper and a few other genetics papers and then the, the Schlein Feld. Um I can't do sim flug immaculate plastics. I can't say that word, uh imaging paper as well because I think that that's actually really high yield. So we'll link all those in the show notes. Thank you so much for joining us, Dr Barris. It's just wonderful. Certainly, it's been insightful, not even just about Fuchs disease, but just even your story and how um at any stages of our career, the hunger for continuing to learn and the ability to do so and contribute in new ways was wonderfully shared. So I appreciate you being here. Thanks for letting me talk about this. So it's like I said, my favorite topic, but also, you know, have that perspective of, of decades. And uh everyone says you, you need to know when to say no, but more importantly, you need to know when to say yes and take advantage of an opportunity. Well, yourself, with good people don't be a weak, you know, the weak link in your chain and, and uh you know, pursue something with Gusto Well said, and well shared. Thank you for being here with us on our podcast. Thank you. Thanks. This has been great. You can find all episodes of the Mayo Clinic Ophthalmology podcast on our website. Thank you for listening and we definitely look forward to sharing more.
