Ground Truths

A leader for conducting rigorous randomized trials of humans along with animal models for understanding nutrition and metabolism, Dr. Kevin Hall is a Senior Investigator at the National Institutes of Health, and Section Chief of the Integrative Physiology Section, NIDDK. In this podcast, we reviewed his prolific body of research a recent publications. The timing of optimizing our diet and nutrition seems apropos, now that we’re in in the midst of the holiday season!Below is a video snippet of our conversation on his ultra-processed food randomized trial.Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! The audios are also available on Apple and Spotify.Note: I’ll be doing a Ground Truths Live Chat on December 11th at 12 N EST, 9 AM PST, so please mark your calendar and join!Transcript with links to publications and audioEric Topol (00:05):Well, hello. This is Eric Topol with Ground Truths, and I'm really delighted to have with me today, Dr. Kevin Hall from the NIH. I think everybody knows that nutrition is so important and Kevin is a leader in doing rigorous randomized trials, which is not like what we usually see with large epidemiologic studies of nutrition that rely on food diaries and the memory of participants. So Kevin, it's really terrific to have you here.Kevin Hall (00:34):Thanks so much for the invitation.Ultra-Processed FoodsEric Topol (00:36):Yeah. Well, you've been prolific and certainly one of the leaders in nutrition science who I look to. And what I thought we could do is go through some of your seminal papers. There are many, but I picked a few and I thought we'd first go back to the one that you published in Cell Metabolism. This is ultra-processed diets cause excessive caloric intake and weight gain. (Main results in graph below.) So maybe you can take us through the principle findings from that trial.Kevin Hall (01:10):Yeah, sure. So that was a really interesting study because it's the first randomized control trial that's investigated the role of ultra-processed foods in potentially causing obesity. So we've got, as you mentioned, lots and lots of epidemiological data that have made these associations between people who consume diets that are very high in ultra-processed foods as having greater risk for obesity. But those trials are not demonstrating causation. I mean, they suggest a strong link. And in fact, the idea of ultra-processed foods is kind of a new idea. It's really sort of appeared on the nutrition science stage probably most prominently in the past 10 years or so. And I first learned about this idea of ultra-processed foods, which is really kind of antithetical to the way most nutrition scientists think about foods. We often think about foods as nutrient delivery vehicles, and we kind of view foods as being the fraction of carbohydrates versus fats in them or how much sodium or fiber is in the foods.Kevin Hall (02:17):And along came this group in Brazil who introduced this new way of classifying foods that completely ignores the nutrient composition and says what we should be doing is classifying foods based on the extent and purpose of processing of foods. And so, they categorize these four different categories. And in the fourth category of this so-called NOVA classification scheme (see graphic below) , they identified something called ultra-processed foods. There's a long formal definition and it's evolved a little bit over the years and continues to evolve. But the basic ideas that these are foods that are manufactured by industries that contain a lot of purified ingredients made from relatively cheap agricultural commodity products that basically undergo a variety of processes and include additives and ingredients that are not typically found in home kitchens, but are typically exclusively in manufactured products to create the wide variety of mostly packaged goods that we see in our supermarkets.Kevin Hall (03:22):And so, I was really skeptical that there was much more about the effects of these foods. Other than that they typically have high amounts of sugar and saturated fat and salt, and they're pretty low in fiber. And so, the purpose of this study was to say, okay, well if there's something more about the foods themselves that is causing people to overconsume calories and gain weight and eventually get obesity, then we should do a study that's trying to test for two diets that are matched for these various nutrients of concern. So they should be matched for the macronutrients, they should be matched for the sugar content, the fat, the sodium, the fiber, and people should just be allowed to eat whatever they want and they shouldn't be trying to change their weight in any way. And so, the way that we did this was, as you mentioned, we can't just ask people to report what they're eating.Kevin Hall (04:19):So what we did was we admitted these folks to the NIH Clinical Center and to our metabolic ward, and it's a very artificial environment, but it's an environment that we can control very carefully. And so, what we basically did is take control over their food environment and we gave them three meals a day and snacks, and basically for a two-week period, they had access to meals that were more than 80% of calories coming from ultra-processed foods. And then in random order, they either received that diet first and give them simple instructions, eat as much as little as you want. We're going to measure lots of stuff. You shouldn't be trying to change your weight or weight that gave them a diet that had no calories from ultra-processed foods. In fact, 80% from minimally processed foods. But again, both of these two sort of food environments were matched for these nutrients that we typically think of as playing a major role in how many calories people choose to eat.Kevin Hall (05:13):And so, the basic idea was, okay, well let's measure what these folks eat. We gave them more than double the calories that they would require to maintain their weight, and what they didn't know was that in the basement of the clinical center where the metabolic kitchen is, we had all of our really talented nutrition staff measuring the leftovers to see what it was that they didn't eat. So we knew exactly what we provided to them and all the foods had to be in our nutrition database and when we compute what they actually ate by difference, so we have a very precise estimate about not only what foods they chose to ate, but also how many calories they chose to eat, as well as the nutrient composition.And the main upshot of all that was that when these folks were exposed to this highly ultra-processed food environment, they spontaneously chose to eat about 500 calories per day more over the two-week period they were in that environment then when the same folks were in the environment that had no ultra-processed foods, but just minimally processed foods. They not surprisingly gained weight during the ultra-processed food environment and lost weight and lost body fat during the minimally processed food environment. And because those diets were overall matched for these different nutrients, it didn't seem to be that those were the things that were driving this big effect. So I think there's a couple of big take homes here. One is that the food environment really does have a profound effect on just the biology of how our food intake is controlled at least over relatively short periods of time, like the two-week periods that we were looking at. And secondly, that there's something about ultra-processed foods that seem to be driving this excess calorie intake that we now know has been linked with increased risk of obesity, and now we're starting to put some of the causal pieces together that really there might be something in this ultra-processed food environment that's driving the increased rates of obesity that we've seen over the past many decades.Eric Topol (07:18):Yeah, I mean I think the epidemiologic studies that make the link between ultra-processed foods and higher risk of cancer, cardiovascular disease, type 2 diabetes, neurodegenerative disease. They're pretty darn strong and they're backed up by this very rigorous study. Now you mentioned it short term, do you have any reason to think that adding 500 calories a day by eating these bad foods, which by the way in the American diet is about 60% or more of the average American diet, do you have any inkling that it would change after a few weeks?Kevin Hall (07:54):Well, I don't know about after a few weeks, but I think that one of the things that we do know about body weight regulation and how it changes in body weight impact both metabolism, how many calories were burning as well as our appetite. We would expect some degree of moderation of that effect eventually settling in at a new steady state, that's probably going to take months and years to achieve. And so the question is, I certainly don't believe that it would be a 500 calorie a day difference indefinitely. The question is when would that difference converge and how much weight would've been gained or lost when people eventually reached that new plateau? And so, that's I think a really interesting question. Some folks have suggested that maybe if you extrapolated the lines a little bit, you could predict when those two curves might eventually converge. That's an interesting thought experiment, but I think we do need some longer studies to investigate how persistent are these effects. Can that fully explain the rise in average body weight and obesity rates that have occurred over the past several decades? Those are open questions.Eric Topol (09:03):Yeah. Well, I mean, I had the chance to interview Chris van Tulleken who wrote the book, Ultra-Processed People and I think you might remember in the book he talked about how he went on an ultra-processed diet and gained some 20, 30 pounds in a short time in a month. And his brother, his identical twin brother gained 50, 60 pounds, and so it doesn't look good. Do you look at all the labels and avoid all this junk and ultra-processed food now or are you still thinking that maybe it's not as bad as it looks?Kevin Hall (09:38):Well, I mean I think that I certainly learned a lot from our studies, and we are continuing to follow this up to try to figure out what are the mechanisms by which this happen. But at the same time, I don't think we can throw out everything else we know about nutrition science. So just because we match these various nutrients in this particular study, I think one of the dangers here is that as you mentioned, there's 60% of the food environment in the US and Great Britain and other places consist of these foods, and so they're unavoidable to some extent, right? Unless you're one of these privileged folks who have your backyard garden and your personal chef who can make all of your foods, I'm certainly not one of those people, but for the vast majority of us, we're going to have to incorporate some degree of ultra-processed foods in our day-to-day diet.Kevin Hall (10:24):The way I sort of view it is, we really need to understand the mechanisms and before we understand the mechanisms, we have to make good choices based on what we already know about nutrition science, that we should avoid the foods that have a lot of sugar in them. We should avoid foods that have a lot of saturated fat and sodium. We should try to choose products that contain lots of whole grains and legumes and fruits and vegetables and things like that. And there's some of those, even in the ultra-processed food category. I pretty regularly consume a microwavable ready meal for lunch. It tends to be pretty high in whole grains and legumes and low in saturated fat and sugar and things like that. But to engineer a food that can heat up properly in a microwave in four minutes has some ultra-processing technology involved there. I would be pretty skeptical that that's going to cause me to have really poor health consequences as compared to if I had the means to eat homemade French fries every day in tallow. But that's the kind of comparison that we have to think about.Eric Topol (11:36):But I think what you're touching on and maybe inadvertently is in that NOVA class four, the bad ultra-processed foods, there's a long, long list of course, and some of those may be worse than others, and we haven't seen an individual ranking of these constituents. So as you're alluding to what's in that microwave lunch probably could be much less concerning than what's in these packaged snacks that are eaten widely. But I would certainly agree that we don't know everything about this, but your study is one of the most quoted studies ever in the ultra-processed food world. Now, let me move on to another trial that was really important. This was published in Nature Medicine and it's about a plant-based diet, which is of course a very interesting diet, low-fat versus an animal-based ketogenic diet. Also looking at energy intake. Can you take us through that trial?Plant-Based, Low Fat Diet vs Animal-Based, Low Carbohydrate Ketogenic DietKevin Hall (12:33):Sure. So it's actually interesting to consider that trial in the context of the trial we just talked about because both of these diets that we tested in this trial were relatively low in ultra-processed foods, and so both of them contained more than a kilogram of non-starchy vegetables as a base for designing these, again, two different food environments. Very similar overall study design where people again were exposed to either diets that were vegan plant-based diet that was really high in starches and was designed to kind of cause big insulin increases in the blood after eating the meals. And the other diet had very, very few carbohydrates of less than 10% in total, and we built on that kind of non-starchy vegetable base, a lot of animal-based products to kind of get a pretty high amount of fat and having very low carbohydrates. Both diets in this case, like I mentioned, were pretty low in ultra-processed foods, but what we were really interested in here was testing this idea that has come to prominence recently, that high carbohydrate diets that lead to really large glucose excursions after meals that cause very high insulin levels after meals are particularly obesogenic and should cause you to be hungrier than compared to a diet that doesn't lead to those large swings in glucose and insulin and the prototypical case being one that's very low in carbohydrate and might increase the level of ketones that are floating around in your blood, which are hypothesized to be an appetite suppressant. Same sort of design, these minimally processed diets that one was very high in carbs and causes large swings in insulin and the other that's very low in carbs and causes increases in ketones.Kevin Hall (14:22):We ask people, again, while you're in one food environment or the other, don't be trying to gain weight or lose weight, eat as much or as little as you'd like, and we're going to basically measure a lot of things. They again, don't know what the primary outcome of the study is. We're measuring their leftovers afterwards. And so, the surprise in this particular case was that the diet that caused the big swings in glucose and insulin did not lead to more calorie consumption. In fact, it led to about 700 calories per day less than when the same people were exposed to the ketogenic diet. Interestingly, both food environments caused people to lose weight, so it wasn't that we didn't see the effect of people over consuming calories on either diet, so they were reading fewer calories in general than they were when they came in, right. They're probably eating a pretty ultra-processed food diet when they came in. We put them on these two diets that varied very much in terms of the macronutrients that they were eating, but both were pretty minimally processed. They lost weight. They ended up losing more body fat on the very low-fat high carb diet than the ketogenic diet, but actually more weight on the ketogenic diet than the low-fat diet. So there's a little bit of a dissociation between body fat loss and weight loss in this study, which was kind of interesting.Eric Topol (15:49):Interesting. Yeah, I thought that was a fascinating trial because plant-based diet, they both have their kind of camps, you know.Kevin Hall (15:57):Right. No, exactly.Immune System Signatures for Vegan vs Ketogenic DietsEric Topol (15:58):There are people who aren't giving up on ketogenic diet. Of course, there's some risks and some benefits and there's a lot of interest of course with the plant-based diet. So it was really interesting and potentially the additive effects of plant-based with avoidance or lowering of ultra-processed food. Now, the more recent trial that you did also was very interesting, and of course I'm only selecting ones that I think are particularly, there are a lot of trials you've done, but this one is more recent in this year where you looked at vegan versus ketogenic diets for the immune signature, immune response, which is really important. It's underplayed as its effect, and so maybe you can take us through that one.[Link to a recent Nature feature on this topic, citing Dr. Hall’s work]Kevin Hall (16:43):Yeah, so just to be clear, it's actually the same study, the one that we just talked about. This is a secondary sort of analysis from a collaboration we had with some folks at NIAID here at the NIH to try to evaluate immune systems signatures in these same folks who wonder what these two changes in their food environment. One is vegan, high carbohydrate low-fat diet and the other, the animal-based ketogenic diet. And again, it was pretty interesting to me that we were able to see really substantial changes in how the immune system was responding. First of all, both diets again seem to have improved immune function, both adaptive and innate immune function as compared to their baseline measurements when they came into the study. So when they're reading their habitual diet, whatever that is typically high in ultra-processed foods, they switched to both of these diets.Kevin Hall (17:39):We saw market changes in their immune system even compared to baseline. But when we then went and compared the two diets, they were actually divergent also, in other words, the vegan diet seemed to stimulate the innate immune system and the ketogenic diet seemed to stimulate the adaptive immune system. So these are the innate immune system can be thought of. Again, I'm not an immunologist. My understanding is that this is the first line defense against pathogens. It happens very quickly and then obviously the adaptive immune system then adapts to a specific pathogen over time. And so, this ability of our diet to change the immune system is intriguing and how much of that has to do with influencing the gut microbiota, which obviously the gut plays a huge role in steering our immune system in one direction versus another. I think those are some really intriguing mechanistic questions that are really good fodder for future research.Eric Topol (18:42):Yeah, I think it may have implications for treatment of autoimmune diseases. You may want to comment about that.Kevin Hall (18:51):Yeah, it's fascinating to think about that the idea that you could change your diet and manipulate your microbiota and manipulate your gut function in a way to influence your immune system to steer you away from a response that may actually be causing your body damage in your typical diet. It's a fascinating area of science and we're really interested to follow that up. I mean, it kind of supports these more anecdotal reports of people with lupus, for example, who've reported that when they try to clean up their diet for a period of time and eliminate certain foods and eliminate perhaps even ultra-processed food products, that they feel so much better that their symptoms alleviate at least for some period of time. Obviously, it doesn't take the place of the therapeutics that they need to take, but yeah, we're really interested in following this up to see what this interaction might be.Eric Topol (19:46):Yeah, it's fascinating. It also gets to the fact that certain people have interesting responses. For example, those with epilepsy can respond very well to a ketogenic diet. There's also been diet proposed for cancer. In fact, I think there's some even ongoing trials for cancer of specific diets. Any comments about that?Kevin Hall (20:10):Yeah, again, it's a really fascinating area. I mean, I think we kind of underappreciate and view diet in this lens of weight loss, which is not surprising because that's kind of where it's been popularized. But I think the role of nutrition and how you can manipulate your diet and still you can have a very healthy version of a ketogenic diet. You can have a very healthy version of a low-fat, high carb diet and how they can be used in individual cases to kind of manipulate factors that might be of concern. So for example, if you're concerned about blood glucose levels, clearly a ketogenic diet is moderating those glucose levels over time, reducing insulin levels, and that might have some positive downstream consequences and there's some potential downsides. Your apoB levels might go up. So, you have to kind of tune these things to the problems and the situations that individuals may face. And similarly, if you have issues with blood glucose control, maybe a high carbohydrate diet might not be for you, but if that's not an issue and you want to reduce apoB levels, it seems like that is a relatively effective way to do that, although it does tend to increase fasting triglyceride levels.Kevin Hall (21:27):So again, there's all of these things to consider, and then when you open the door beyond traditional metabolic health markers to things like inflammation and autoimmune disease as well as some of these other things like moderating how cancer therapeutics might work inside the body. I think it's a really fascinating and interesting area to pursue.Eric Topol (21:55):No question about it. And that also brings in the dimension of the gut microbiome, which obviously your diet has a big influence, and it has an influence on your brain, brain-gut axis, and the immune system. It's all very intricate, a lot of feedback loops and interactions that are not so easy to dissect, right?Kevin Hall (22:16):Absolutely. Yeah, especially in humans. That's why we rely on our basic science colleagues to kind of figure out these individual steps in these chains. And of course, we do need human experiments and carefully controlled experiments to see how much of that really translates to humans, so we need this close sort of translational partnership.On the Pathogenesis of Obesity, Calories In and Calories OutEric Topol (22:35):Yeah. Now, you've also written with colleagues, other experts in the field about understanding the mechanisms of pathogenesis of obesity and papers that we'll link to. We're going to link to everything for what we've been discussing about calories in, calories out, and that's been the longstanding adage about this. Can you enlighten us, what is really driving obesity and calories story?Kevin Hall (23:05):Well, I co-organized a meeting for the Royal Society, I guess about a year and a half ago, and we got together all these experts from around the world, and the basic message is that we have lots of competing theories about what is driving obesity. There's a few things that we all agree on. One is that there is a genetic component. That adiposity in a given environment is somewhere between 40% to 70% heritable, so our genes play a huge role. It seems like there's certain genes that can play a major role. Like if you have a mutation in leptin, for example, or the leptin receptor, then this can have a monogenic cause of obesity, but that's very, very rare. What seems to be the case is that it's a highly polygenic disease with individual gene variants contributing a very, very small amount to increased adiposity. But our genes have not changed that much as obesity prevalence has increased over the past 50 years. And so, something in the environment has been driving that, and that's where the real debates sort of starts, right?Kevin Hall (24:14):I happen to be in the camp that thinks that the food environment is probably one of the major drivers and our food have changed substantially, and we're trying to better understand, for example, how ultra-processed foods which have risen kind of in parallel with the increased prevalence of obesity. What is it about ultra-processed foods that tend to drive us to overconsume calories? Other folks focus maybe more on what signals from the body have been altered by the foods that we're eating. They might say that the adipose tissue because of excess insulin secretion for example, is basically driven into a storage mode and that sends downstream signals that are eventually sensed by the brain to change our appetite and things like that. There's a lot of debate about that, but again, I think that these are complementary hypotheses that are important to sort out for sure and important to design experiments to try to figure out what is more likely. But there is a lot of agreement on the idea that there's something in our environment has changed.Kevin Hall (25:17):I think there's even maybe a little bit less agreement of exactly what that is. I think that there's probably a little bit more emphasis on the food environment as opposed to there are other folks who think increased pollution might be driving some of this, especially endocrine disrupting chemicals that have increased in prevalence. I think that's a viable hypothesis. I think we have to try to rank order what we think are the most likely and largest contributors. They could all be contributing to some extent and maybe more so in some people rather than others, but our goal is to try to, maybe that's a little simple minded, but let's take the what I think is the most important thing and let's figure out the mechanisms of that most important thing and we'll, number one, determine if it is the most important thing. In my case, I think something about ultra-processed foods that are driving much of what we're seeing. If we could better understand that, then we could both advise consumers to avoid certain kinds of foods because of certain mechanisms and still be able to consume some degree of ultra-processed foods. They are convenient and tasty and relatively inexpensive and don't require a lot of skill and equipment to prepare. But then if we focus on the true bad guys in that category because we really understand the mechanisms, then I think that would be a major step forward. But that's just my hypothesis.Eric Topol (26:43):Well, I’m with you actually. Everything I've read, everything I've reviewed on ultra-processed food is highly incriminating, and I also get frustrated that nothing is getting done about it, at least in this country. But on the other hand, it doesn't have to be either or, right? It could be both these, the glycemic index story also playing a role. Now, when you think about this and you're trying to sort out calories in and calories out, and let's say it's one of your classic experiments where you have isocaloric proteins and fat and carbohydrate exactly nailed in the different diets you're examining. Is it really about calories or is it really about what is comprising the calorie?Kevin Hall (27:29):Yeah, so I think this is the amazing thing, even in our ultra-processed food study, if we asked the question across those people, did the people who ate more calories even in the ultra-processed diet, did they gain more weight? The answer is yes.Kevin Hall (27:44):There's a very strong linear correlation between calorie intake and weight change. I tend to think that I started my career in this space focusing more on the metabolism side of the equation, how the body's using the calories and how much does energy expenditure change when you vary the proportion of carbs versus fat, for example. The effect size is there, they might be there, but they're really tiny of the order of a hundred calories per day. What really struck me is that when we just kind of changed people's food environments, the magnitude of the effects are like we mentioned, 500 to 700 calories per day differences. So I think that the real trick is to figure out how is it that the brain is regulating our body weight in some way that we are beginning to understand from a molecular perspective? What I think is less well understood is, how is that food intake control system altered by the food environment that we find ourselves in?The Brain and GLP-1 DrugsKevin Hall (28:42):There are a few studies now in mice that are beginning to look at how pathways in the brain that have been believed to be related to reward and not necessarily homeostatic control of food intake. They talk to the regions of the brain that are related to homeostatic control of food intake, and it's a reciprocal sort of feedback loop there, and we're beginning to understand that. And I think if we get more details about what it is in our foods that are modulating that system, then we'll have a better understanding of what's really driving obesity and is it different in different people? Are there subcategories of obesity where certain aspects of the food environment are more important than others, and that might be completely flipped in another person. I don't know the answer to that question yet, but it seems like there are certain common factors that might be driving overall changes in obesity prevalence and how they impact this reward versus homeostatic control systems in the brain, I think are really fascinating questions.Eric Topol (29:43):And I think we're getting much more insight about this circuit of the reward in the brain with the food intake, things like optogenetics, many ways that we're getting at this. And so, it's fascinating. Now, that gets me to the miracle drug class GLP-1, which obviously has a big interaction with obesity, but of course much more than that. And you've written about this as well regarding this topic of sarcopenic obesity whereby you lose a lot of weight, but do you lose muscle mass or as you referred to earlier, you lose body fat and maybe not so much muscle mass. Can you comment about your views about the GLP-1 family of drugs and also about this concern of muscle mass loss?Kevin Hall (30:34):Yeah, so I think it's a really fascinating question, and we've been trying to develop mathematical models about how our body composition changes with weight gain and weight loss for decades now. And this has been a long topic, one of the things that many people may not realize is that people with obesity don't just have elevated adiposity, they also have elevated muscle mass and lean tissue mass overall. So when folks with obesity lose weight, and this was initially a pretty big concern with bariatric surgery, which has been the grandfather of ways that people have lost a lot of weight. The question has been is there a real concern about people losing too much weight and thereby becoming what you call sarcopenic? They have too little muscle mass and then they have difficulties moving around. And of course, there are probably some people like that, but I think what people need to realize is that folks with obesity tend to start with much higher amounts of lean tissue mass as well as adiposity, and they start off with about 50% of your fat-free mass, and the non-fat component of your body is skeletal muscle.Kevin Hall (31:45):So you're already starting off with quite a lot. And so, the question then is when you lose a lot of weight with the GLP-1 receptor agonist or with bariatric surgery, how much of that weight loss is coming from fat-free mass and skeletal muscle versus fat mass? And so, we've been trying to simulate that using what we've known about bariatric surgery and what we've known about just intentional weight loss or weight gain over the years. And one of the things that we found was that our sort of expectations for what's expected for the loss of fat-free mass with these different drugs as well as bariatric surgery, for the most part, they match our expectations. In other words, the expected amount of fat loss and fat free mass loss. The one outlier interestingly, was the semaglutide study, and in that case, they lost more fat-free mass than would be expected.Kevin Hall (32:44):Now, again, that's just raising a little bit of a flag that for whatever reason, from a body composition perspective, it's about a hundred people underwent these repeated DEXA scans in that study sponsored by Novo Nordisk. So it's not a huge number of people, but it's enough to really get a good estimate about the proportion of weight loss. Whether or not that has functional consequences, I think is the open question. There's not a lot of reports of people losing weight with semaglutide saying, you know what? I'm really having trouble actually physically moving around. I feel like I've lost a lot of strength. In fact, it seems to be the opposite, right, that the quality of the muscle there seems to be improved. They seem to have more physical mobility because they've lost so much more weight, that weight had been inhibiting their physical movement in the past.Kevin Hall (33:38):So it's something to keep an eye on. It's an open question whether or not we need additional therapies in certain categories of patients, whether that be pharmacological, there are drugs that are interesting that tend to increase muscle mass. There's also other things that we know increase muscle mass, right? Resistance exercise training, increase this muscle mass. And so, if you're really concerned about this, I certainly, I'm not a physician, but I think it's something to consider that if you go on one of these drugs, you might want to think about increasing your resistance exercise training, maybe increasing the protein content of your diet, which then can support that muscle building. But I think it's a really interesting open question about what the consequences of this might be in certain patient populations, especially over longer periods of time.Dietary Protein, Resistance Exercise, DEXA ScansEric Topol (34:30):Yeah, you've just emphasized some really key points here. Firstly, that resistance exercise is good for you anyway. And get on one of these drugs, why don't you amp it up or get it going? The second is about the protein diet, which it'd be interesting to get your thoughts on that, but we generally have too low of a protein diet, but then there are some who are advocating very high protein diets like one gram per pound, not just one gram per kilogram. And there have been studies to suggest that that very high protein diet could be harmful, but amping up the protein diet, that would be a countering thing. But the other thing you mentioned is a DEXA scan, which can be obtained very inexpensively, and because there's a variability in this muscle mass loss if it's occurring, I wonder if that's a prudent thing or if you just empirically would just do the things that you mentioned. Do you have any thoughts about that?Kevin Hall (35:32):Yeah, that's really a clinical question that I don't deal with on a day-to-day basis. And yeah, I think there's probably better people suited to that. DEXA scans, they're relatively inexpensive, but they're not readily accessible to everyone. I certainly wouldn't want to scare people away from using drugs that are now known to be very effective for weight loss and pretty darn safe as far as we can tell, just because they don't have access to a DEXA scanner or something like that.Eric Topol (36:00):Sure. No, that makes a lot of sense. I mean, the only reason I thought it might be useful is if you're concerned about this and you want to track, for example, how much is that resistant training doing?Kevin Hall (36:13):But I think for people who have the means to do that, sure. I can't see any harm in it for sure.Continuous Glucose Sensors?Eric Topol (36:19):Yeah. That gets me to another metric that you've written about, which is continuous glucose tracking. As you know, this is getting used, I think much more routinely in type one insulin diabetics and people with type 2 that are taking insulin or difficult to manage. And now in recent months there have been consumer approved that is no prescription needed, just go to the drugstore and pick up your continuous glucose sensor. And you've written about that as well. Can you summarize your thoughts on it?Kevin Hall (36:57):Yeah, sure. I mean, yeah, first of all, these tools have been amazing for people with diabetes and who obviously are diagnosed as having a relative inability to regulate their glucose levels. And so, these are critical tools for people in that population. I think the question is are they useful for people who don't have diabetes and is having this one metric and where you target all this energy into this one thing that you can now measure, is that really a viable way to kind of modulate your lifestyle and your diet? And how reliable are these CGM measurements anyway? In other words, do they give the same response to the same meal on repeated occasions? Does one monitor give the same response as another monitor? And those are the kinds of experiments that we've done. Again, secondary analysis, these trials that we talked about before, we have people wearing continuous glucose monitors all the time and we know exactly what they ate.Kevin Hall (37:59):And so, in a previous publication several years ago, we basically had two different monitors. One basically is on the arm, which is the manufacturer's recommendation, the other is on the abdomen, which is the manufacturer's recommendation. They're wearing them simultaneously. And we decided just to compare what were the responses to the same meals in simultaneous measurements. And they were correlated with each other thankfully, but they weren't as well predictive as you might expect. In other words, one device might give a very high glucose reading to consuming one meal and the other might barely budge, whereas the reverse might happen for a different meal. And so, we asked the question, if we were to rank the glucose spikes by one meal, so we have all these meals, let's rank them according to the glucose spikes of one device. Let's do the simultaneous measurements with the other device.Kevin Hall (38:53):Do we get a different set of rankings? And again, they're related to each other, but they're not overlapping. They're somewhat discordant. And so, then the question becomes, okay, well if I was basically using this one metric to kind of make my food decisions by one device, I actually start making different decisions compared to if I happen to have been wearing a different device. So what does this really mean? And I think this sort of foundational research on how much of a difference you would need to make a meaningful assessment about, yeah, this is actionable from a lifestyle perspective, even if that is the one metric that you're interested in. That sort of foundational research I don't think has really been done yet. More recently, we asked the question, okay, let's ignore the two different devices. Let's stick to the one where we put it on our arm, and let's ask the question.Kevin Hall (39:43):We've got repeated meals and we've got them in this very highly regimented and controlled environment, so we know exactly what people ate previously. We know the timing of the meals, we know when they did their exercise, we know how much they were moving around, how well they slept the night before. All of these factors we could kind of control. And the question that we asked in that study was, do people respond similarly to the same meal on repeated occasions? Is that better than when you actually give them very different meals? But they match overall for macronutrient content, for example. And the answer to that was surprisingly no. We had as much variability in the glucose response to the same person consuming the same meal on two occasions as a whole bunch of different meals. Which suggests again, that there's enough variability that it makes it difficult to then recommend on for just two repeats of a meal that this is going to be a meal that's going to cause your blood glucose to be moderate or blood glucose to be very high. You're going to have to potentially do this on many, many different occasions to kind of figure out what's the reliable response of these measurements. And again, that foundational research is typically not done. And I think if we're really going to use this metric as something that is going to change our lifestyles and make us choose some meals other than others, then I think we need that foundational research. And all we know now is that two repeats of the same meal is not going to do it.Eric Topol (41:21):Well, were you using the current biosensors of 2024 or were you using ones from years ago on that?Kevin Hall (41:27):No, we were using ones from several years ago when these studies were completed. But interestingly, the variability in the venous measurements to meal tests is also very, very different. So it's probably not the devices per se that are highly variable. It's that we don't really know on average how to predict these glucose responses unless there's huge differences in the glycemic load. So glycemic load is a very old concept that when you have very big differences in glycemic load, yeah, you can on average predict that one kind of meal is going to give rise to a much larger glucose excursion than another. But typically these kind of comparisons are now being made within a particular person. And we're comparing meals that might have quite similar glycemic loads with the claim that there's something specific about that person that causes them to have a much bigger glucose spike than another person. And that we can assess that with a couple different meals.Eric Topol (42:31):But also, we know that the spikes or the glucose regulation, it's very much affected by so many things like stress, like sleep, like exercise. And so, it wouldn't be at all surprising that if you had the exact same food, but all these other factors were modulated that it might not have the same response. But the other thing, just to get your comment on. Multiple groups, particularly starting in Israel, the Weizmann Institute, Eran Segal and his colleagues, and many subsequent have shown that if you give the exact same amount of that food, the exact same time to a person, they eat the exact same amount. Their glucose response is highly heterogeneous and variable between people. Do you think that that's true? That in fact that our metabolism varies considerably and that the glucose in some will spike with certain food and some won’t.Kevin Hall (43:29):Well, of course that's been known for a long time that there's varying degrees of glucose tolerance. Just oral glucose tolerance tests that we've been doing for decades and decades we know is actually diagnostic, that we use variability in that response as diagnostic of type 2 diabetes.Eric Topol (43:49):I'm talking about within healthy people.Kevin Hall (43:53):But again, it's not too surprising that varying people. I mean, first of all, we have a huge increase in pre-diabetes, right? So there's various degrees of glucose tolerance that are being observed. But yeah, that is important physiology. I think the question then is within a given person, what kind of advice do we give to somebody about their lifestyle that is going to modulate those glucose responses? And if that's the only thing that you look at, then it seems like what ends up happening, even in the trials that use continuous glucose monitors, well big surprise, they end up recommending low carbohydrate diets, right? So that's the precision sort of nutrition advice because if that's the main metric that's being used, then of course we've all known for a very long time that lower carbohydrate diets lead to a moderated glucose response compared to higher carbohydrate diets. I think the real question is when you kind of ask the issue of if you normalize for glycemic load of these different diets, and there are some people that respond very differently to the same glycemic load meal compared to another person, is that consistent number one within that person?Kevin Hall (45:05):And our data suggests that you're going to have to repeat that same test multiple times to kind of get a consistent response and be able to make a sensible recommendation about that person should eat that meal in the future or not eat that meal in the future. And then second, what are you missing when that becomes your only metric, right? If you're very narrowly focused on that, then you're going to drive everybody to consume a very low carbohydrate diet. And as we know, that might be great for a huge number of people, but there are those that actually have some deleterious effects of that kind of diet. And if you're not measuring those other things or not considering those other things and put so much emphasis on the glucose side of the equation, I worry that there could be people that are being negatively impacted. Not to mention what if that one occasion, they ate their favorite food and they happen to get this huge glucose spike and they never eat it again, their life is worse. It might've been a complete aberration.Eric Topol (46:05):I think your practical impact point, it's excellent. And I think one of the, I don't know if you agree, Kevin, but one of the missing links here is we see these glucose spikes in healthy people, not just pre-diabetic, but people with no evidence of glucose dysregulation. And we don't know, they could be up to 180, 200, they could be prolonged. We don't know if the health significance of that, and I guess someday we'll learn about it. Right?Kevin Hall (46:36):Well, I mean that's the one nice thing is that now that we have these devices to measure these things, we can start to make these correlations. We can start to do real science to say, what a lot of people now presume is the case that these spikes can't be good for you. They must lead to increased risk of diabetes. It's certainly a plausible hypothesis, but that's what it is. We actually need good data to actually analyze that. And at least that's now on the table.Eric Topol (47:04):I think you're absolutely right on that. Well, Kevin, this has been a fun discussion. You've been just a great leader in nutrition science. I hope you'll keep up your momentum because it's pretty profound and I think we touched on a lot of the uncertainties. Is there anything that I didn't ask you that you wish I did?Kevin Hall (47:23):I mean, we could go on for hours, I'm sure, Eric, but this has been a fascinating conversation. I really appreciate your interest. Thank you.Eric Topol (47:30):Alright, well keep up the great stuff. We'll be following all your work in the years ahead, and thanks for joining us on Ground Truths today.**************************************Footnote, Stay Tuned: Julia Belluz and Kevin Hall have a book coming out next September titled “WHY WE EAT? Thank you for reading, listening and subscribing to Ground Truths.If you found this fun and informative please share it!All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. I welcome all comments from paid subscribers and will do my best to respond to them and any questions.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.Note on Mass Exodus from X/twitter:Many of you have abandoned the X platform for reasons that I fully understand. While I intend to continue to post there because of its reach to the biomedical community, I will post anything material here in the Notes section of Ground Truths on a daily basis and cover important topics in the newsletter/analyses. You can also find my posts at Bluesky: @erictopol.bsky.social, which is emerging as an outstanding platform for sharing life science. Get full access to Ground Truths at erictopol.substack.com/subscribe

Below is a brief video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! This one has embedded one of my favorite TikTok’s from Will. There are several links to others in the transcript. The audios are also available on Apple and Spotify.Transcript with links to both audio and videos, commencement addresses, NEJM article coverageEric Topol (00:06):Hi, it's Eric Topol from Ground Truths, and I've got an amazing couple with me today. It's Will Flanary and Kristin Flanary, the Glaucomfleckens. I've had the chance to get to know them a bit through Knock Knock, Hi! which is their podcast. And of course, everyone knows Dr. Glaucomflecken from his TikTok world and his other about 4 million followers on Instagram and Twitter and all these other social media, and YouTube. So welcome.Will Flanary (00:43):Thanks for having us.Kristin Flanary (00:44):Thank you. Happy to be here.By Way of BackgroundEric Topol (00:45):Yeah. Well, this is going to be fun because I'm going to go a quick background so we can go fast forward because we did an interview back in early 2022.Kristin Flanary (00:56):Yes.Eric Topol (00:57):And what you've been doing since then is rocking it. You're like a meteoric, right. And it was predictable, like rarefied talent and who couldn't love humor, medical humor, but by way of background, just for those who are not up to speed. I guess you got your start, Will, as a class clown when your mother was a teacher in the sixth grade.Will Flanary (01:22):Yep, yep. I misbehaved a little bit. It helped that I still made good grades, but I cut up a bit in class.Eric Topol (01:32):And then you were already in the comedy club circuits doing standup in Houston as an 18-year-old.Will Flanary (01:40):It was all amateur stuff, nothing, just dabble in it and trying to get better. I was always kind of naturally funny just with my friend group and everything. I loved making people laugh, but doing standups is a whole different ball game. And so, I started doing that around Houston as a high school senior and kept that going through college and a little bit into med school.Kristin Flanary (02:02):Houston was a good training ground, right? That where Harris Wittels was also coming up.Will Flanary (02:07):Yeah. A lot of famous comedians have come through Houston. Even going back to Bill Hicks back in the, was that the 80s, I think? Or 90s?Eric Topol (02:17):Well, and then of course, it was I think in 2020 when you launched Dr. Glaucomflecken, I think. Is that right?Will Flanary (02:28):That's when it really started to take off. I was on Twitter telling jokes back in 2016.Kristin Flanary (02:39):GomerBlog before that, that's actually where it was born.Will Flanary (02:41):I was doing satire writing. I basically do what I'm doing now, but in article form, trying to be The Onion of medicine. And then the pandemic hit, started doing video content and that's really with lockdown. That's when, because everybody was on social media, nobody had anything else to do. So it was right place, right time for me and branching out into video content.On to Medical School Commencement AddressesEric Topol (03:11):Alright, so that's the background of some incredible foundation for humor. But since we last got together, I'll link the Medicine and the Machine interview we did back then. What has been happening with you two is nothing short of incredible. I saw your graduation speeches, Will. Yale in 2022, I watched the UCSF in 2023 and then the University of Michigan in 2024. Maybe there's other ones I don't even know.Kristin Flanary (03:45):There’s a few others.Will Flanary (03:45):There's a few. But I feel like you've done, I'm sure your fair share of commencement addresses as well. It's kind of hard to come up with different ways to be inspirational to the next generation. So fortunately, we have together, we have some life experiences and learned a thing or two by doing all of this social media stuff and just the things we've been through that I guess I have enough things to say to entertain an interest.Eric Topol (04:18):Well, you're being humble as usual, but having watched those commencement addresses, they were the best medical commencement addresses I've ever seen. And even though you might have told us some of the same jokes, they were so great that it was all right. Yeah, and you know what is great about it is you've got these, not the students, they all love you of course, because they're probably addicted to when's your next video going to get posted.(04:44):But even the old professors, all the family members, it's great. But one of the things I wanted to get at. Well, I'll start with the graduation speeches, because you were such an inspiration, not just with humor, but your message. And this gets back to you as a couple and the tragedies you've been through. So you really, I think, got into this co-survivor story and maybe Kristin, since you are the co-survivor of two bouts of Will’s testicular cancer, and then the sudden cardiac death. I mean, people don't talk about this much, so maybe you could help enlighten us.Tragedies and Being a Co-SurvivorKristin Flanary (05:26):Yeah, it’s funny because the experience of being a co-survivor is nothing new. It’s as long as we've had human beings, we've had co-survivors. But the concept around it and giving it a name and a label, a framework to be able to think about it, that is what I think is new and what people haven't talked about before. So co-survivor is just this idea that when a medical trauma happens to a patient, the patient has their experience and if they survive it, they are a survivor and they have a survivor experience. And also, most people are closely attached to at least one other person, if not many. And those people are co-surviving the medical event along with the survivor. That event is happening in their lives as was happening to them too. If someone comes in with a patient to the hospital, that person, you can just assume by default that their lives are pretty intimately or profoundly intertwined or else why would that person be there? And so, thinking of it as there's the patient and then there's also a co-patient, that family members in the past have only been thought of as caregivers if they've been thought of at all. And that is certainly one aspect of the role, but it's important to remember that whatever it is that's happening to the patient is also affecting the family members' lives in a really deep and profound way.Eric Topol (07:04):That's really helpful. Now, the fact that you recognize that in your graduation speech, Will, I think is somewhat unique. And of course, some of the other things that you touched on like playing to your creativity and the human factors, I mean, these are so important messages.Will Flanary (07:23):Well, in the discussion about co-survivorship and because I talk about that whenever I do my keynotes and when I do the commencement addresses, but all credit goes to Kristin for really being the driving force of this idea for me and for many others because as a physician, we take care of patients. Our focus is always on the patient. And it really wasn't until this happened to me and my family and Kristin in particular that I started to understand exactly what she's talking about and this idea. And so, Kristin gets a lot of credit for just really bringing that term and that idea to the forefront.Eric Topol (08:09):Yeah, well, you saved his life. It's just not many have that bond. And then the other thing I just want to mention now, you've been recognized by the American Heart Association and a whole bunch of other organizations awarded because of your advocacy for CPR. And you even mentioned that I think in one of your commencement addresses.Will Flanary (08:31):Yeah, I tried to get the crowd to do CPR. Like team up, partner up, and it kind of fell flat. It wasn't quite the right time, I think, to try to do a mass class on CPR. So maybe next time.Eric Topol (08:47):Right. Well, so you had this foundation with the Glaucomflecken General Hospital and taking on 37 specialties and all these incredible people that became part of the family, if you will, of spoof on medicine and your alter ego and these videos that you would do. And sometimes you have three or four different alter egos in there playing out, but now you've branched into new things. So one which is an outgrowth of what we were just talking about. You've been on this country tour, Wife & Death.“Wife and Death,” A Nationwide TourKristin Flanary (09:28):Yes.Eric Topol (09:29):Wife and death. I mean, yeah, I guess we can make the connect of how you named it that, but what is it you've been selling out in cities all over the country, and by the way, I'm really upset you haven't come to San Diego, but tell us about wife and death.Will Flanary (09:44):Yeah. Well, we have this amazing story and all these medical challenges we've been through, and then developing the Glaucomflecken brand and universe, and we've done keynotes together for years, and then we thought, let's have more fun with it. Let's do keynotes. They're great. We can get our message out, but sometimes they're just a bit stuffy. It's an academic environment.Kristin Flanary (10:15):They're usually at seven in the morning also, so that's the downside.Will Flanary (10:21):So we thought, let's just put together our own live show. Let's put together something that we could just creatively, we can do whatever we want with it. I could dress up as characters, Kristin, who has these beautiful writing and monologues that she's put together around her experience and just to create something that people can come into a theater and just experience this wide range of emotions from just laughter to tears of all kinds, and just have them feel the story and enjoy this story. Fortunately, it has a happy ending because I'm still alive and it's been so much fun. The audiences have been incredible. Mostly healthcare, but even some non-healthcare people show up, and we've been blown away by the response. Honestly, we should have done bigger theaters. That's our lesson for the first go round.Eric Topol (11:21):I saw you had to do a second show in Pittsburgh.Will Flanary (11:24):We did.Kristin Flanary (11:26):That one sold out too. Something about Pittsburgh, that was a good crowd, and there was a lot of them.Will Flanary (11:33):It was almost like in Pittsburgh, they rarely ever get any internet comedian ophthalmologists that come through. I don't know.Eric Topol (11:41):Well, I see you got some still to come in Denver and Chicago. This is amazing. And I wondered who was coming and I mean, it's not at all surprising that there'd be this phenomenal popularity. So that's one thing you've done that's new, which is amazing. And of course, it's a multidimensional story. The one that shocked me, I have to tell you, shocked me, was the New England Journal partnership. The New England Journal is the most stodgy, arrogant, I mean so difficult. And not only that.Kristin Flanary (12:17):You said that. Not us.Partnering with the New England Journal of Medicine!Eric Topol (12:19):Yeah, yeah. They'll get this too. They know we don't get along that well, but that's okay. You even made fun of journals. And now you're partnering with the New England Journal, God's greatest medical journal, or whatever. Tell us about that.Will Flanary (12:39):Well, so one thing that I really enjoy doing, and I've done it with my US healthcare system content is almost like tricking people into learning things. And so, if you make something funny, then people will actually sit there and listen to what you have to say about deductibles and physician-owned hospitals and all these inner workings. DIR fees and pharmacy, all these things that are really dry topics. But if you can make them funny, all of a sudden people will actually learn and listen to it. And the New England Journal of Medicine, they approached me with an idea. Basically just to take one or two of their trials per month. And I just make a skit out of that trial with the idea being to help disseminate some of the research findings that are out there, because I guess it's getting harder and harder for people to actually read, to sit down and read a journal article.(13:43):And so, I have to credit them for having this idea and thinking outside the box of a different way to get medical information and knowledge out to the masses. And you're absolutely right, that I have been critical of journals, and particularly I've been critical of the predatory nature of some of the larger journals out there, like Elsevier. I've specifically named Elsevier, Springer, these journals that have a 40% profit margin. And I certainly thought about that whenever I was looking into this partnership. And the reason I was okay with doing it with the New England Journal is because they're a nonprofit, first of all, so they're run by the Massachusetts Medical Society. That's the publisher for that journal. And so, I feel okay partnering with them because I feel like they're doing it in a much better way than some of the bigger journal corporations out there.Kristin Flanary (14:54):Well, and also part of the deal that we negotiated was that those articles that you make skits about those will be available open access.Will Flanary (15:03):Oh yeah. That was a prerequisite. Yes. It was like, if I'm going to do this, the articles that I'm talking about need to be free and readily available. That's part of it.Eric Topol (15:14):I think you've done about five already, something like that. And I watched them, and I just was blown away. I mean, the one that got me where I was just rolling on the floor, this one, the Belantamab Mafodotin for Multiple Myeloma. And when you were going on about the Bortezomib, Dexamethasone. We'll link to this. I said, oh my God.Will Flanary (15:40):Yeah. The joke there is, you don't have any idea how long it took me to say those things that quickly. And so, I was writing this skit and I'm like, wouldn't it be funny if somehow that triggered a code stroke in the hospital because this person is saying all these random words that don't have any meaning to anybody. Man, I tell you, I am learning. Why would I ever need to know any of this information as an ophthalmologist? So it's great. I know all this random stuff about multiple myeloma that I probably would never have learned otherwise.Kristin Flanary (16:21):It's the only way, you won't read a journal either.Eric Topol (16:23):Well, and if you read the comments on the post. These doctors saying, this is the only way they want to get journal information from now on.Will Flanary (16:33):Which is double-edged sword, maybe a little bit. Obviously, in a 90 second skit, there's no way I'm going to cover the ins and outs of a major trial. So it's really, in a lot of ways, it's basically like, I call it a comedy abstract. I’m not going much further than an abstract, but hopefully people that are actually interested in the topic can have their interest piqued and want to read more about it. That's kind of the idea.Eric Topol (17:06):Yeah. Well, they're phenomenal. We'll link to them. People will enjoy them. I know, because I sure did. And tenecteplase for stroke and all that you've done. Oh, they're just phenomenal.Will Flanary (17:20):Every two weeks we come out with a new one.Eric Topol (17:24):And that is basically between the fact that you are now on the commencement circuit of the top medical schools and doing New England Journal videos on their articles. You've crossed a line from just making fun of insurance companies and doctors of specialties.Kristin Flanary (17:44):Oh, he has crossed many lines, Dr. Topol.Eric Topol (17:46):Yeah. Oh yeah. Now you've done it, really. Back two years ago when we convened, actually it's almost three, but you said, when's it going to be your Netflix special?Will Flanary (18:02):Oh, gosh.Eric Topol (18:02):Is that in the works now?Will Flanary (18:04):Well, I'll tell you what's in the works now.Kristin Flanary (18:06):Do you know anyone at Netflix?Will Flanary (18:09):A New Animated SeriesNo. We're working on an animated series.Eric Topol (18:12):Oh, wow. Wow.Will Flanary (18:13):Yeah. All these characters. It's basically just this fictional hospital and all these characters are very cartoonish, the emergency physician that wears the bike helmet and everything. So it's like, well, what do we have together? What do we, Kristin and I have time for? And it wasn't like moving to LA and trying to make a live action with actors and do all, which is something we probably could have tried to do. So instead, we were like, let's just do an animated series.Kristin Flanary (18:48):Let's have someone else do the work and draw us.Will Flanary (18:51):So we've worked with a writer for the first time, which was a fun process, and putting together a few scripts and then also an animator. We learned a lot about that process. Kristin and I are doing the voiceovers. And yeah, it's in process.Kristin Flanary (19:10):We're the only actors we could afford.Will Flanary (19:12):Right, exactly.Eric Topol (19:13):I can't wait to see it. Now when will it get out there?Will Flanary (19:17):Well, we're hoping to be able to put it out on our YouTube channel sometime early next year. So January, February, somewhere around there. And then we can't fund the whole thing ourselves. So the idea is that we do this, we do this pilot episode, and then we'll see what kind of interest we can generate.Eric Topol (19:37):Well, there will be interest. I am absolutely assured of that. Wow.Will Flanary (19:42):Let us know if you know anybody at the Cartoon Network.Kristin and Will Flanary (19:45):Yeah, we're open to possibilities. Whatever, Discovery channel. I don't know.Eric Topol (19:51):You've gotten to a point now where you're ready for bigger things even because you're the funniest physician couple in medicine today.Kristin Flanary (20:05):Well, that's a very low bar, but thank you.Will Flanary (20:08):There are some funny ones out there, but yeah, I appreciate that.Eric Topol (20:11):Well, I'm a really big comedy fan. Every night I watch the night before, since I'm old now, but of Colbert and Jimmy Kimmel, just to hear the monologues. Trevor Noah, too. And I can appreciate humor. I'll go to see Sebastian Maniscalco or Jim Gaffigan. That's one of the things I was going to ask you about, because when you do these videos, you don't have an audience.Will Flanary (20:39):Oh yeah.Eric Topol (20:40):You're making it as opposed to when you are doing your live shows, commencement addresses and things like that. What's the difference when you're trying to be humorous, and you have no audience there?Will Flanary (20:55):Well, whenever I'm filming a skit, it's just all production. In fact, I feel like it's funny. I think it's funny, but it's really not until I see the response to it, or I show Kristin, or what I have is where I really know if it's going to work. It's great to put the content out there and see the responses, but there's nothing like live interaction. And that's why I keep coming back to performing. And Kristin's been a performer too in her life. And I think we both really enjoy just the personal interaction, the close interaction, the response from people to our story.Kristin Flanary (21:36):We do most of our work alone in this room. I do a lot of writing. He does a lot of playing.Will Flanary (21:44):Dress up.Kristin Flanary (21:44):All the people in his head, and we do that very isolated. And so, it's very lovely to be able to actually put names to faces or just see human bodies instead of just comments on YouTube.Will Flanary (21:59):Meet people.Kristin Flanary (21:59):It's really nice.Will Flanary (22:01):We’ve been doing meet and greets at the live shows and seeing people come up wearing their costumes.Eric Topol (22:07):Oh, wow.Will Flanary (22:11):Some of them talk about how they tell us their own stories about their own healthcare and talk about how the videos help them get through certain parts of the pandemic or a difficult time in their life. And so, it reinforces that this means something to a lot of people.Kristin Flanary (22:29):It's been really fun for me, and probably you too, but to get to see the joy that he has brought so many people. That's really fun to see in person especially.Eric Topol (22:42):No question. Now, when you're producing it together, do you ever just start breaking into laughter because it's you know how funny this is? Or is it just you're on kind of a mission to get it done?Will Flanary (22:54):Well, the skits I do by myself. And sometimes when I'm writing out the skit, when I'm writing the skit itself, I will laugh at myself sometimes. Not often, but sometimes they're like, oh, I know that's really funny. I just wrote a skit that I'm actually going to be debuting. I'm speaking at the American Academy of PM&R, so the big PM&R conference. I'm writing a skit, it's How to Ace your PM&R residency interview.Will Flanary (23:28):I was writing up that skit today and kind of chuckling to myself. So sometimes that happens, but whenever we do our podcast together, we definitely have outtakes.Kristin Flanary (23:38):Oh yeah, we've got some.Will Flanary (23:40):We crack each other up.Kristin Flanary (23:41):We do.Will Flanary (23:42):Sometimes we're getting a little punchy toward the end of the day.Eric Topol (23:47):And how is the Knock Knock, Hi! podcast going?Will Flanary (23:51):It's awesome. Yeah.Kristin Flanary (23:52):Yeah. It's a really fun project.Will Flanary (23:54):We still enjoy. You can work with your spouse and in close proximity and still be happily married. So it's doable everyone.Kristin Flanary (24:06):That's right. And we're in that phase of life that's really busy. We've got kids, we've got a gazillion jobs. House, my parents are around, and so it's like the only time all week that we actually get to sit down and talk to each other. So it's actually kind of like a part of our marriage at this point.Will Flanary (24:28):We’re happy to involve the public in our conversations, but we couldn't do it because we have all these things going on, all our hands and all these little places. We can't do it without a team.Kristin Flanary (24:41):Yeah, absolutely.Will Flanary (24:41):And that's the thing that I've learned, because I've always been a very loner type content creator. I just wanted to do it all myself. It's in my head and I have trouble telling others, describing what's in my head. And Kristin and our producers have helped me to be able to give a little bit of control to others who are really good at what they do. And that's really the only way that we've been able to venture out into all these different things we've talked about.Eric Topol (25:12):Well, I think it comes down to, besides your ability to get to people in terms of their laughter receptors, you have this incisive observer capability. And that's one of the things I don't, I can't fathom because when you can understand the nuances of each specialty or of each part of healthcare, and you haven't necessarily interacted with these specialists or at least in recent years, but you nail it every time. I don't know how you do it, really that observational, is that a central quality of a comedian, you think?Will Flanary (25:52):There's definitely a big part of that. You got to get the content from somewhere. But for the specialties, it's really first about just getting the personalities down. And that doesn't change over time.Kristin Flanary (26:08):Or around the world.Will Flanary (26:09):Or around the world. We hear from people from all over the world about, oh, it's the same in Guatemala as it is in the US.Kristin Flanary (26:18):Surgeons are the same.Will Flanary (26:19):Yeah.Kristin Flanary (26:20):Emergency is the same.Will Flanary (26:21):Which has been really cool to see. But so, I draw on my experience interacting with all these specialties back in my med school and intern days. You're right, as an ophthalmologist, we don't get out very much.Eric Topol (26:33):No.Will Flanary (26:35):So very few people have ever seen an ophthalmologist. We do exist. But then beyond that, I do have to include some actual medical things. And so, I actually, I do a lot of research. I find myself learning more about other fields sometimes than I do in my own field. So especially the further out I get from med school, I know less and less.Eric Topol (27:00):Yeah, that's what I was thinking. But you're always spot on. It's interesting to get that global perspective from both of you. Now you're still doing surgery and practicing ophthalmology. Have you reduced it because this has just been taking off so much more over the recent years or keeping it the same?Will and Kristin Flanary (27:21):Nope, I’m still. Do you know how many years I had to come along on all of this medical training? He is not allowed to give this up.Will Flanary (27:29):I know there's something called a sunk cost fallacy, but this is no fallacy. There's enough of a sunk cost. I got to stick with it. No, I still enjoy it. That's the thing. It actually, it informs my comedy, it grounds me. All of the social media stuff is built upon this medical foundation that I have. And if I stopped practicing, I guess I could maybe cut back. But I'm not planning on doing that. If I stop practicing medicine, I feel like it would make my content less.Kristin Flanary (28:07):Authentic.Will Flanary (28:08):Less authentic, yeah. That's a good way to put it.Eric Topol (28:09):Yeah, no, that makes a lot of sense. That's great you can get that balance with all the things you're doing.Will Flanary (28:17):And if I stop practicing medicine, they're not going to invite me to any more commencement addresses, Dr. Topol. So I got to draw the line somewhere.Eric Topol (28:28):One of the statements you made at some point earlier was, it was easier to go to become a doctor than to try to be a comedian. And yeah, I mean you proven that.Will Flanary (28:38):A lot of ways. That's true.Eric Topol (28:40):Wow. I am pretty awestruck about the rarefied talent that you bring and what you both have done for medicine today. And the thing is, you're so young, you have so much time ahead to have an impact.Will Flanary (28:57):You hear that Kristin, we're young. Look at that.Kristin Flanary (29:00):That's getting less and less true.Will Flanary (29:01):Kristin, she just turned 40. It's right around the corner for me. So I don't know.Will Flanary (29:11):We got some years left.Eric Topol (29:12):You're like young puppies. Are you kidding? You're just getting started. But no, I think that what you brought to medicine in terms of comedy, there's no other entity, no person or people like you have done. And just the last thing I want to ask you about is, you have a platform for advocacy. You've been doing that. We talked about co-survivor. We talked about nurturing the human qualities in physicians like creativity and also taking on the insurance companies, which are just monstrous. I'll link a couple of those, but the brain MRI one or the Texaco.Will Flanary (29:54):Texaco Mike.Eric Topol (29:55):Yeah, that one is amazing. But there is so many. I mean, you've just taken them apart and they deserve every bit of it. Do you have any other targets for advocacy or does that just kind of come up as things go?Will Flanary (30:08):It kind of comes up as things go. There's things I keep harping on. The prior authorization reform, which I've helped in a couple of different states. There's a lot of good people around the country doing really good work on prior authorization and reforming that whole process. And I've been able to just play a small part in that in a couple of different ways. And it's been really fun to do that. And so, I do plan on continuing that crusade as it were. There's certain things I'd like to see. I've been learning more about what pharmacists are dealing with as well as a physician. Unfortunately, we are very separate in a lot of ways and just how we come up in medicine. And so, I have had my eyes opened a lot to what community pharmacists are dealing with. For all the terrible things that we have to deal with as physicians in the healthcare system. Pharmacists have just as much, if not more of the things that they're doing that are threatening their livelihoods. And so, I had love to see some more reform on the PBM side of things, pharmacy benefit managers, Caremark, Optum, all of them. They're causing lots of problems.Eric Topol (31:24):I couldn't agree with you more. In fact, I'm going to have Mark Cuban on in a few weeks and we're going to get into that. But the pharmacists get abused by these chains.Will Flanary (31:33):Oh, it's bad. It's really bad.Eric Topol (31:35):Horrible, horrible. I feel, and every time I am in a drugstore working with one of them, I just think what a tough life they have to deal with.Will Flanary (31:45):I guess from an advocacy standpoint, the good news is that there's never a shortage of terrible injustices that are being foisted upon the public and physicians and healthcare workers.Kristin Flanary (31:59):Yes. The US healthcare system is ripe for advocacy.Will Flanary (32:01):Yes. And that's a lesson that I tell people too, and especially the med students coming up, is like, there's work to be done and get in touch with your state societies and there's always work to be done.Eric Topol (32:18):Now you've stayed clear of politics. Totally clear, right?Will Flanary (32:24):For the most part, yeah. Yeah. It depends on what you consider politics. It depends on what you consider politics.Eric Topol (32:32):It being election day, you haven't made any endorsements.Will Flanary (32:36):I haven't. And I don't know. I can only handle so much. I've got my things that I really care about. Of course I'm voting, but I want to talk on the things that I feel like I have the expertise to talk about. And I think there's nothing wrong with that. Everybody can't have an opinion on everything, and it means something. So I am happy to discuss the things that I have expertise about, and I'm always on the side of the patient and wanting to make life better for our patients. And that's the side I'm on.Kristin Flanary (33:25):I think also he never comes out and explicitly touches on certain topics, but it's not hard to tell where he falls.Will Flanary (33:34):If you really want read into it all.Kristin Flanary (33:38):It's not like it's a big secret.Eric Topol (33:40):I thought that too. I'm glad you mentioned it, Kristin. But it doesn't come out wide open. But yeah, it's inferred for sure.Eric Topol (33:49):I think the point being there is that because you have a reach, I think there's no reach that it has 4 million plus people by your posts and no less the tours and keynotes and everything else. So you could go anywhere but sticking to where you're well grounded, it makes a lot of sense. And anyway, I am going to be staying tuned. This is our two-year checkup. I'm hoping you're going to come to San Diego on your next tour.Kristin Flanary (34:21):We're working on 2025 plans.Will Flanary (34:23):Oh, we got more shows coming up. And we'll hit up other parts of the country too.Eric Topol (34:28):I feel like I got to meet you in person, give you a hug or something. I just feel like I'm missing out there. But it's just a joy to have had a chance to work with you on your podcast. And thanks for coming back on one of mine. There's lots of podcasts out there, but having you and joining you is such fun. So thank you.Will Flanary (34:54):This has been great. Thank you for having us.Kristin Flanary (34:55):Yeah, thank you.*****************************************Thank you for reading, listening and and subscribing to Ground Truths.If you found this fun and informative please share it! Yes, laughter is the best medicine.All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.Note on Exodus from X/twitter:Many of you have abandoned the X platform for reasons that I understand. While I intend to continue to post there because of its reach to the biomedical community, I will post anything material here in the Notes section of Ground Truths on a daily basis and cover important topics in the newsletter/analyses. Get full access to Ground Truths at erictopol.substack.com/subscribe

Above is a brief video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to audio and external citationsEric Topol (00:06):Well, hello it's Eric Topol with Ground Truths, and I'm really delighted to welcome Dr. Rachael Bedard, who is a physician geriatrician in New York City, and is actually much more multidimensional, if you will. She's a writer. We're going to go over some of her recent writings. She's actually quite prolific. She writes in the New Yorker, New York Magazine, New York Times, New York Review of Books. If it has New York in front of it, she's probably writing there. She's a teacher. She works on human rights, civil rights, criminal justice in the prison system. She's just done so much that makes her truly unique. That's why I really wanted a chance to meet her and talk with her today. So welcome, Rachael.Rachael Bedard (00:52):Thank you, Dr. Topol. It's an honor to be here.Eric Topol (00:55):Well, please call me Eric and it's such a joy to have a chance to get acquainted with you as a person who is into so many different things and doing all of them so well. So maybe we'd start off with, because you're the first geriatrician we've had on this podcast.Practicing Geriatrics and Internal MedicineEric Topol (01:16):And it’s especially apropos now. I wanted maybe to talk about your practice, how you got into geriatrics, and then we'll talk about the piece you had earlier this summer on aging.Rachael Bedard (01:32):Sure. I went into medicine to do social justice work and I was always on a funny interdisciplinary track. I got into the Mount Sinai School of Medicine through what was then called the Humanities and Medicine program, which was an early acceptance program for people who were humanities focused undergrads, but wanted to go into medicine. So I always was doing a mix of politics and activist focused work, humanities and writing, that was always interested in being a doctor. And then I did my residency at the Cambridge Health Alliance, which is a social medicine program in Cambridge, Massachusetts, and my chief residency there.(02:23):I loved being an internist, but I especially loved taking care of complex illness and I especially loved taking care of complex illness in situations where the decision making, there was no sort of algorithmic decision-making, where you were doing incredibly sort of complex patient-centered shared decision making around how to come up with treatment plans, what the goals of care were. I liked taking care of patients where the whole family system was sort of part of the care team and part of the patient constellation. I loved running family meetings. I was incredibly lucky when I was senior resident and chief resident. I was very close with Andy Billings, who was one of the founders of palliative care and in the field, but also very much started a program at MGH and he had come to work at Cambridge Hospital in his sort of semi-retirement and we got close and he was a very influential figure for me. So all of those things conspired to make me want to go back to New York to go to the Sinai has an integrated geriatrics and palliative care fellowship where you do both fellowships simultaneously. So I came to do that and just really loved that work and loved that medicine so much. There was a second part to your question.Eric Topol (03:52):Is that where you practice geriatrics now?Rachael Bedard (03:55):No, now I have ever since finishing fellowship had very unusual practice settings for a geriatrician. So right out of fellowship, I went to work on Rikers Island and then New York City jail system, and I was the first jail based geriatrician in the country, which is a sort of uncomfortable distinction because people don't really like to think about there being a substantial geriatric population in jails. But there is, and I was incredibly lucky when I was finishing fellowship, there was a lot of energy around jail healthcare in New York City and I wrote the guy who was then the CMO and said, do you think you have an aging problem? And he said, I'm not sure, but if you want to come find out, we'll make you a job to come find out. And so, that was an incredible opportunity for someone right out of fellowship.(04:55):It meant stepping off the sort of academic track. But I went and worked in jail for six years and took care of older folks and people with serious illness in jail and then left Rikers in 2022. And now I work in a safety net clinic in Brooklyn that takes care of homeless people or people who have serious sort of housing instability. And that is attached to Woodhull Hospital, which is one of the public hospitals in New York City. And there I do a mix of regular internal medicine primary care, but I preferentially see the older folks who come through, which is a really interesting, painful, complicated patient population because I see a fair amount of cognitive impairment in folks who are living in the shelter system. And that's a really hard problem to address.Frailty, The Aged, and LongevityEric Topol (05:54):Well, there's a theme across your medical efforts. It seems to me that you look after the neglected folks, the prisoners, the old folks, the homeless people. I mean that's kind of you. It's pretty impressive. And there's not enough of people like you in the medical field. Now, no less do you do that, but of course you are a very impressive author, writer, and of many topics I want to get into with you, these are some recent essays you've written. The one that piqued my interest to start to understand who you were and kind of discover this body of work was the one that you wrote related to aging and President Biden. And that was in New York Times. And I do want to put in a quote because as you know very well, there's so much interest in longevity now.Eric Topol (06:51):Interrupting the aging process, and this one really stuck with me from that op-ed, “Time marches forward, bodies decline, and the growing expectation that we might all live in perfect health until our 100th birthdays reflects a culture that overprizes longevity to the point of delusion.” So maybe if you could tell us, that was a rich piece, you got into frailty, you related it to the issues that were surrounding President Biden who at that time had not withdrawn from the race. But what were you thinking and what are your thoughts about the ability to change the aging process?Rachael Bedard (07:36):I am very interested in, I mean, I'm incredibly interested in the science of it. And so, I guess I think that there are a few things.(07:49):One thing is that the framework that, the part that gives me pause the most is this framework that anything less than perfect health is not a life worth living. So if you're going to have a long life, life should not just be long and sort of healthy in relative terms to your age cohort, but healthy that when you're 80 you should feel like you have the health of a 45-year-old is my understanding of the culture of longevity science. And while I understand why that's aspirational and everybody worry about my body's decline, I think it's a really problematic thing to say that sick bodies are bodies that have disability or people who have cognitive difference are somehow leading lesser lives or lives that are not meaningful or not worth living. I think it's a very, very slippery slope. It puts you in a place where it sort of comes up against another trend or another emerging cultural trend, which is really thinking a lot about physician-assisted suicide and end of life choices.(09:04):And that in some ways that conversation can also be very focused on this idea that there's just no way that it's worth living if you're sick. And that's just not true, I think, and that's not been true for many, many, many of my patients, some of whom have lived with enormous disability and incredible burden of illness, people who are chronically seriously ill and are still leading lives that for them and for the people who love them are filled with meaning. So that's my concern about the longevity stuff. I'm interested in the science around the longevity stuff for sure. I'm interested in, I think we're living in this really interesting moment where there's so much happening across so many of the chronic disease fields where the things that I think have been leading to body decay over the last several decades for the majority of the population, we're sort of seeing a lot of breakthroughs in multiple fronts all at once. And that's really exciting. I mean, that's really exciting. And so, certainly if it's possible to make it to 100 in wonderful health, that's what I'd wish for all of us. But to hold it up as the standard that we have to achieve, I think is both unrealistic and a little myopic.Eric Topol (10:28):Yeah. Well, I certainly agreed with that and I think that that particular essay resonated so well and you really got into frailty and the idea about how it can be potentially prevented or markedly delayed. And I think before we move on to one of those breakthroughs that you were alluding to, any comments about the inevitability of frailty in people who are older, who at some point start to get the dwindles, if you will, what do you have to say about that?Rachael Bedard (11:11):Well, from a clinical standpoint, I guess the caveat versus that not everybody becomes frail and dwindles exactly. Some people are in really strong health up until sort of their final years of life or year of life and then something happens, they dwindle quickly and that's how they die. Or some people die of acute events, but the vast majority of us are going to become more frail in our final decades than we are in our middle decades. And that is the normal sort of pattern of wear and tear on the body. And it is an extraordinary framework, I think frailty because the idea of this sort of syndrome of things where it's really not a disease framework, it is a syndrome framework and it's a framework that says many, many small injuries or stressors add up to create a lot of stress and change in a body and trauma for our body. And once you are sort of past a tipping point of an amount of stress, it's very hard to undo those things because you are not sort of addressing one pathologic process. You're addressing, you're trying to mitigate many processes all at once.(12:31):When I wrote that piece, it was inspired by the conversation surrounding President Biden's health. And I was particularly struck by, there was a huge amount of clinical speculation about what was going on with him, right? I'm sure you remember there were people, there was all of this talk about whether he had Parkinson's and what his cognitive status was. And it felt to me like there was an opportunity to do some public education around the idea that you need not have one single sort of smoking gun illness to explain decline. What happens to most of us is that we're going to decline in many small ways sort of simultaneously, and it's going to impact function when it tips over a little bit. And that pattern of decline is not going to be steady day over day worsening. It's going to be up and down. And if you slept better the night before, you might have a better day the next day. And if you slept badly, you might have a worse day. And without knowing anything specific about his clinical situation, it felt like a framework that could explain so much of what we were seeing in public. And it was important also, I think to say that nothing was necessarily being hidden from anybody and that this is the kind of thing that, this has accumulated stress over time that then presents suddenly all at once after having been submerged.Eric Topol (14:01):Yeah, you reviewed that so well about the wear and tear and everything related to that. And before I move on to the second topic, I want to just circle back to something you alluded to, which is when Peter Attia wrote about this medicine 3.0 and how you would be compressed and you'd have no comorbidities, you'd have no other illnesses and just fall off the cliff. As a geriatrician, do you think that that is even conceivable?Rachael Bedard (14:35):No. Do you think it is?Eric Topol (14:37):No, but I just wanted to check the reality. I did challenge on an earlier podcast and he came up with his pat answer. But no, there's no evidence of that, that maybe you can delay if there ever was a way to do that. But I think there's this kind of natural phenomena that you just described, and I'll refer people also to that excellent piece that you get into it more.Rachael Bedard (15:06):Peter Attia, I mean, he is certainly the sort of standard bearer in my mind of that movement and that science or that framework of thinking about science. And there's stuff in there that's really valuable. The idea of thinking about lifestyle in your middle decades is having meaningful impact on how you will age, what your final years will look like. That seems intuitively true, I think. And so, thinking about his emphasis on exercise, I mean, his emphasis on exercise is particularly intense and not super achievable for the average person, but the idea that you should sort of be thinking about keeping your body strong because it will decline eventually. And so, you want to do that from a higher peak. That makes a lot of sense to me. The idea that where we sort of draw pathologic disease cutoffs is obviously a little bit arbitrary. And so, wanting to think about optimizing pre-disease states and doing prevention, that's obviously, I think pretty appealing and interesting. It's just really in an evidence free zone.Ozempic for the IndigentEric Topol (16:18):Yeah, that's what I confronted him with, of course, he had a different perspective, but you summed that up really well. Now let's switch to a piece you had in New York magazine. It was entitled, What If Ozempic Is Just a Good Thing? And the reason, of course, this ties into the first thing we're discussing. There's even talk now, the whole GLP-1 family of drugs with the dual triple receptors, pills to come that we're going to be able to interrupt a path towards Alzheimer's and Parkinson's. Obviously you've already seen impact in heart disease, liver disease, kidney disease way before that, diabetes and obesity. So what are your thoughts? Because you wrote a very interesting, you provided a very interesting perspective when you wrote that one.Rachael Bedard (17:11):So that piece I wrote because I have this unbelievably privileged, interesting clinical practice. In New York City, there is public health insurance basically available to anybody here, including folks who are undocumented. And the public hospital system has pharmacies that are outpatient pharmacies that have, and New York Medicaid is very generous and they arranged through some kind of brilliant negotiating. I don't quite know how to make Ozempic to make semaglutide available to people who met criteria which meant diabetes plus obesity, but that we could prescribe it even for our very, very poor patients and that they would be able to get it reliably, that we would have it in stock. And I don't know how many other practices in the country are able to reliably provide GLP-1s to marginalized folks like that. I think it feels like a really rare opportunity and a very distinct perspective.(18:23):And it has just been the most amazing thing, I think to have this class of drugs come along that, as you say, addresses so many problems all at once with at least in my prescribing experience, a relatively mild tolerable side effect profile. I have not had patients who have become incredibly sick with it. And for folks where making that kind of impact on their chronic illness is so critical to not just their longevity, but their disease status interacts so much with their social burden. And so, it's a very meaningful intervention I think around poverty actually.(19:17):I really feel that almost all of the popular press about it has focused very much on use amongst the wealthy and who's getting it off label and how are they getting it and which celebrities are taking it, and what are the implications for eating and diet culture and for people who have eating disorders. And that's a set of questions that's obviously sort of interesting, but it's really interesting in a very rarefied space. There's an unbelievable diabetes epidemic in this country, and the majority of people who have diabetes are not the people who are getting written about over and over again in those pieces. It's the patients that I take care of, and those people are at risk of ending up on dialysis or getting amputations. And so, having a tool this effective is really miraculous feeling to me.Eric Topol (20:10):Well, it really gives me some hope because I don't know any program like that one, which is the people who need it the most. It's getting provided for them. And we have been talking about a drug that costs a thousand dollars a month. It may get down to $500 a month, but that's still a huge cost. And of course, there's not much governmental coverage at this point. There might be some more for Medicare, Medicaid, whatever in the future, but it's really the original criteria of diabetes, and it took almost 20 years to get to where we are right now. So what's so refreshing here is to know that there's at least one program that is helping to bridge the inequities and to not make it as was projected, which was, as you say, for celebrities and wealthy people more exclusively, so that's great. And we still don't know about the diverse breadth of these effects, but as you well know, there's trials in Alzheimer's. I spoke to Steve Horvath recently on the podcast and he talked about how it's reset the epigenetic clock, GLP-1.Rachael Bedard (21:24):Does he think so?Eric Topol (21:26):Whoa. Yeah, there was evidence that was just presented about that. I said, well, if that does correspond to aging, the thing that we spoke about first, that would be very exciting.Rachael Bedard (21:37):It’s so wild. I mean, it's so exciting. It's so exciting to me on so many levels. And one of them is it's just exploding my mental model of disease pathogenesis, and it's making me think, oh my goodness, I have zero idea actually how metabolism and the brain and sort of cardiovascular disease, all of those things are obviously, what is happening in the interplay between all of those different systems. It's really so much more complicated and so much more interdependent than I understood it to be. I am really optimistic about the Alzheimer's trial. I am excited for those results, and I think we're going to keep seeing that it prevents different types of tumors.Eric Topol (22:33):Yeah, no, and that's been shown at least certainly in obese people, that there’s cancers that gets way reduced, but we never had a potent anti-inflammatory that works at the brain and systemically like this before anyone loses the weight, you already see evidence.Long Covid and ME/CFS(22:50):It is pretty striking. Now, this goes back to the theme that was introduced earlier about looking after people who are neglected, who aren't respected or generally cared for. And I wanted to now get into Long Covid and the piece you wrote in the New Yorker about listening to patients, called “what would it mean for scientists to listen to patients?” And maybe you can talk about myalgic encephalitis/chronic fatigue (ME/CFS), and of course Long Covid because that's the one that is so pervasive right now as to the fact that these people don't get respect from physicians. They don't want to listen to their ailments. There's no blood tests, so there's no way to objectively make a diagnosis supposedly. And they're basically often dismissed, or their suffering is discounted. Maybe you can tell us again what you wrote about earlier this year and any updated thoughts.Rachael Bedard (24:01):Have you had my friend Harlan Krumholz on the show to talk about the LISTEN study?Eric Topol (24:04):Not yet. I know Harlan very well. Yes.Eric Topol (24:11):I know Akiko Iwasaki very well too. They’re very, very close.Rachael Bedard (24:14):So, Akiko Iwasaki and Harlan Krumholz at Yale have been running this research effort called the LISTEN study. And I first learned about it sometime in maybe late 2021. And I had been really interested in the emerging discourse around chronic illness in Long Covid in the 2021. So when we were past the most acute phase of the pandemic, and we were seeing this long tail of sequelae in patients, and the conversation had really shifted to one that was about sort of trying to define this new syndrome, trying to understand it, trying to figure out how you could diagnose it, what were we seeing sort of emerge, how are we going to draw boxes around it? And I was so interested in the way that this syndrome was really patient created. It came out of patients identifying their own symptoms and then banning together much, much faster than any kind of institutional science can ever work, getting into message boards together or whatever, and doing their own survey work and then coming up with their own descriptive techniques about what they were experiencing.(25:44):And then beyond that, looking into the literature and thinking about the treatments that they wanted to try for themselves. Patients were sort of at the forefront of every step of recognizing, defining, describing this illness presentation and then thinking about what they wanted to be able to do for themselves to address it. And that was really interesting to me. That was incredibly interesting to me. And it was also really interesting because by, I don't know exactly when 2021 or 2022, it was already a really tense landscape where it felt like there were real factions of folks who were in conflict about what was real and what wasn't real, how things ought to be studied, who ought to be studying them, what would count as evidence in this realm. And all of those questions were just really interesting to me. And the LISTEN study was approaching them in this really thoughtful way, which was Harlan and Akiko sort of partnering really closely with patients who enrolled.(26:57):And it's a decentralized study and people could enroll from all over the world. There's a portion of patients who do have their blood work evaluated, but you can also just complete surveys and have that data count towards, and those folks would be from anywhere in the world. Harlan did this amazing, amazing work to figure out how to collect blood samples from all over the country that would be drawn at home for people. So they were doing this decentralized study where people from their homes, from within the sort of circumstances of their lives around their chronic illness could participate, which that was really amazing to me. And then they were partnering really thoughtfully with these patients just to figure out what questions they wanted to ask, how they wanted to ask them, and to try to capture a lot of multimodal data all at once.(27:47):Survey data, journaling so people could write about their own experience in a freeform journal. They were collecting blood samples, and they were holding these town halls. And the town halls were on a regular basis, Harlan and Akiko, and anybody who was in the study could come on, could log onto a Zoom or whatever, and Harlan and Akiko and their research staff would talk about how things were going, what they were working on, what questions they had, what the roadblocks were, and then they would answer questions from their participants as the study was ongoing. And I didn't think that I had ever heard of something quite like that before. Have you ever heard of anything?Eric Topol (28:32):No. I mean, I think this is important to underscore, this was the first condition that was ever patient led, patient named, and basically the whole path was laid by the patient. So yes, and everything you summarize is so well as to the progress that's been made. Certainly, Harlan and Akiko are some of the people that have really helped lead the way to do this properly as opposed to, unfortunately one and a half billion dollars that have been put to the NIH for the RECOVER efforts that haven't yet led to even a significant clinical trial, no less a validated treatment. But I did think it was great that you spotlighted that just because again, it's thematic. And that gets me to the fourth dimension, which is you're the first prison doctor I've ever spoken to. And you also wrote a piece about that called, “the disillusionment of a Rikers Island Doctor” in the New Yorker, I think it was. And I wonder if you could tell us, firstly, now we're four years into Covid, you were for a good part of that at Rikers Island, I guess.The Rikers Island Prison Doctor During CovidRachael Bedard (30:00):I was, yeah.Eric Topol (30:00):Yeah. And what could be a more worrisome spot to be looking after people with Covid in a prison? So maybe you could just give us some insight about all that.Rachael Bedard (30:17):Yeah, it was really, I mean, it was the wildest time, certainly in my career probably that I'll ever have. In the end of February and beginning of March of 2020, it became very apparent to my colleagues and I that it was inevitable that this virus that was in Wuhan and in Italy was coming to the US. And jails are, we sort of jokingly described them as the worst cruise ships in the world. They are closed systems where everybody is eating, sleeping, going to the bathroom, everything on top of each other. There's an incredible amount of excess human contact in jails and prisons because people don't have freedom of movement and they don't get to do things for themselves. So every single, somebody brings you your mail, somebody brings you your meals, somebody brings you your medications. If you're going to move from point A to point B, an officer has to walk you there. So for a virus that was going to spread through what we initially thought was droplets and then found out was not just droplets but airborne, it was an unbelievably high-risk setting. It's also a setting where folks tend to be sicker than average for their age, that people bring in a lot of comorbidity to the setting.(31:55):And it's not a setting that does well under stress. I mean, jails and prisons are places that are sort of constitutionally violent, and they're not systems that adapt easily to emergency conditions. And the way that they do adapt tends to be through repressive measures, which tends to be violence producing rather than violence quelling. And so, it was just an incredibly scary situation. And in mid-March, Rikers Island, the island itself had the highest Covid prevalence of anywhere in the country because New York City was the epicenter, and Rikers was really the epicenter within New York. It was a wild, wild time. Our first seriously ill patient who ended up getting hospitalized. That was at that time when people were, we really didn't understand very much about what Covid looked like. And there was this guy sitting on the floor and he said, I don't know. I can't really get up.(32:59):I don't feel well. And he had an O2 stat of 75 or something. He was just incredibly hypoxic. It's a very scary setting for that kind of thing, right? It's not a hospital, it's not a place where you can't deliver ICU level care in a place like that. So we were also really worried about the fact that we were going to be transferring all of these patients to the city hospitals, which creates a huge amount of extra burden on them because an incarcerated patient is not just the incarcerated patients, the officers who are with that person, and there are special rules around them. They have to be in special rooms and all of these things. So it was just a huge systems crisis and really painful. And we, early on, our system made a bunch of good guesses, and one of our good guesses was that we should just, or one of our good calls that I entirely credit my bosses with is that they understood that we should advocate really hard to get as many people out as we could get out. Because trying to just manage the population internally by moving people around was not going to be effective enough, that we really need to decant the setting.(34:18):And I had done all of this work, this compassionate release work, which is work to get people who are sick out of jail so that they can get treatment and potentially die in a free setting. And so, I was sort of involved in trying to architect getting folks who were sort of low enough security risks out of jail for this period of time because we thought that they would be safer, and 1500 people left Rikers in the matter of about six weeks.Rachael Bedard (34:50):Which was a wild, wild thing. And it was just a very crazy time.Eric Topol (34:56):Yeah. Well, the word compassion and you go together exceptionally well. I think if we learn about you through your writings, that really shines through and what you've devoted your care for people in these different domains. This is just a sampling of your writings, but I think it gives a good cross section. What makes you write about a particular thing? I mean, obviously the Rikers Island, you had personal experience, but why would you pick Ozempic or why would you pick other things? What stimulates you to go after a topic?Rachael Bedard (35:42):Sometimes a lot of what I write about relates to my personal practice experience in some way, either to geriatrics or death and dying or to the criminal justice system. I've written about people in death row. I've written about geriatrics and palliative care in sort of a bunch of different ways. I am interested in topics in medicine where things are not yet settled, and it feels very of the moment. I'm interested in what the discourse is around medicine and healthcare. And I am interested in places where I think the discourse, not just that I'm taking a side in that discourse, but where I think the framework of the discourse is a little bit wrong. And I certainly feel that way about the Ozempic discourse. And I felt that way about the discourse around President Biden, that we're having not just a conversation that I have a strong opinion about, but a conversation that I think is a little bit askew from the way that we ought to be thinking about it.Eric Topol (36:53):And what I love about each of these is that you bring all that in. You have many different points of view and objective support and they're balanced. They're not just trying to be persuasive about one thing. So, as far as I know, you're extraordinarily unique. I mean, we are all unique, but you are huge standard deviations, Rachael. You cover bases that are, as I mentioned, that are new to me in terms of certainly this podcast just going on for now a couple of years, that is covering a field of both geriatrics and having been on the corrections board and in prison, particularly at the most scary time ever to be working in prison as a physician. And I guess the other thing about you is this drive, this humanitarian theme. I take it you came from Canada.Rachael Bedard (37:59):I did.Eric Topol (37:59):You migrated to a country that has no universal health.Rachael Bedard (38:03):That's right.Eric Topol (38:03):Do you ever think about the fact that this is a pretty pathetic situation here?Rachael Bedard (38:08):I do. I do think about it all the time.Eric Topol (38:10):In our lifetime, we'll probably never see universal healthcare. And then if you just go a few miles up north, you pretty much have that.Rachael Bedard (38:18):Yeah, if you've lived in a place that has universal healthcare and you come here, it's really sort of hard to ever get your mind around. And it has been an absolute possessing obsession of my entire experience in the US. I've now been here for over 20 years and still think it is an unbelievably, especially I think if you work with marginalized patients and how much their lack of access compounds the difficulty of their lives and their inability to sort of stabilize and feel well and take care of themselves, it's really frustrating.Advice for Bringing Humanities to Medicine in a CareerEric Topol (39:14):Yeah, yeah. Well, I guess my last question to you, is you have weaved together a career that brings humanities to medicine, that doesn't happen that often. What's your advice to some of the younger folks in healthcare as to how to pull that off? Because you were able to do it and it's not easy.Rachael Bedard (39:39):My main advice when people ask me about this, especially to students and to residents who are often the people who are asking is to write when you can or pursue your humanities interests, your critical interests, whatever it is that you're doing. Do it when you can, but trust that your career is long and that you have a lot of time. Because the thing that I would say is I didn't start publishing until I was in fellowship and before that I was busy because I was learning to become a doctor. And I think it's really important that my concern about being a doctor who's a hybrid, which so many of us are now. A doctor or something else is you really do want to be a good doctor. And becoming a good doctor is really hard. And it's okay if the thing that is preoccupying you for the first 10 years of your training is becoming a great clinician. I think that's a really, really important thing to do. And so, for my first 10 years for med school and residency and chief residency and fellowship, I would write privately on the side a fair amount, but not try to publish it, not polish that work, not be thinking in sort of a careerist way about how I was going to become a doctor writer because I was becoming a doctor. And that was really preoccupying.(41:08):And then later on, I both sort of had more time and mental space to work on writing. But also, I had the maturity, I think, of being a person who was comfortable in my clinical identity to have real ideas and insights about medicine that felt different and unique to me as opposed to, I barely understand what's going on around me and I'm trying to pull it together. And that's how I would've been if I had done it more, I think when I was younger. Some people are real prodigies and can do it right out the gate, but I wasn't like that.Eric Topol (41:42):No, no, I think that's really sound advice because that's kind of the whole foundation for everything else. Is there a book in the works or will there be one someday?Rachael Bedard (41:53):There may be one someday. There is not one now. I think about it all the time. And that same advice applies, which is I believe in being a late bloomer and taking your time and figuring out what it is you really want to do.Eric Topol (42:10):Yeah. Well, that's great. Have I missed anything? And obviously we only can get to know you in what, 40 minutes to some extent, but have I not touched on something that you want to bring up?Rachael Bedard (42:23):No, I don't think so. Thank you for this conversation. It's been lovely.Eric Topol (42:28):No, I really enjoyed it. I'll be following your career. It's extraordinary already and you've got decades ahead to make an impact and obviously thinking of all these patients that you look after and have in the past, it’s just extraordinary. So what a joy to talk with you, Rachael, and I hope we'll have a chance to do that again in the times ahead.Rachael Bedard (42:51):Me as well. Thank you so much for inviting me.**********************************************Thank you for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly help fund our education and summer internship programs.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don’t want to bother you with an email for content that you’re not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

Superimposed on an impressive body of work on the blood-brain-barrier and immune system, Prof Akassoglou and her collaborators just published an elegant study in Nature that centered on the direct binding os the SARS-CoV-2 spike protein to fibrin with marked downstream pro-inflammatory effects. The findings and potential treatments have implications beyond Covid, Long Covid to other neurologic diseases.Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to audio and to relevant papers, graphicsEric Topol (00:07):Well, hello this is Eric Topol with Ground Truths, and with me today is Katerina Akassoglou. She is at the Gladstone Institute and she is a remarkable neuroimmunologist who has been doing extraordinary work for three decades to unravel the interactions between the brain, blood vessels and the role of inflammation. So Katerina, there's a lot to discuss, so welcome.Katerina Akassoglou (00:40):Thank you. Thank you so much. It's a great pleasure to join.By Way of BackgroundEric Topol (00:43):It's really interesting going back in your career. First of all, we're thankful that you immigrated here from Greece, and you have become one of the leading scientists in this discipline of important discipline of neuroimmunology, which is not just about Covid that we're going to talk about, but Alzheimer's and neurodegenerative diseases. This is a really big hot area and you're definitely one of the leaders. And what I was impressed is that all these years that you've been working on the integrity of the blood-brain barrier, the importance of fibrinogen and fibrin, and then comes along the Covid story. So maybe what we can do is start with that, which is you've made your mark in understanding this whole interaction between what can get into the brain, through the blood-brain barrier and incite inflammation. So this has been something that you've really taken to the extreme knowledge base. So maybe we can start with your work there before we get into the important seminal Nature paper that you recently published.Katerina Akassoglou (01:57):Yes, of course. So since very early on, I was still a graduate student when we made the first discovery and at the time was like mid-90s, so it was really ahead of its time. That dysregulation of cytokine expression in the brain of mice was sufficient to induce the whole cascade of events, triggering neurodegeneration, demyelination in pathological alterations, very reminiscent of multiple sclerosis pathology. And it was really hard to publish that study at the time because it was not yet accepted that this regulation of the immune system modeling the brain can be linked to neurodegeneration. So that was 1995 when we made that discovery, and I became really interested, what are the pathogenic triggers that actually polarized the immune cells in the brain? So with this, of course, this transgenic animal was expressing TNF, it was an artificially made animal that we made, but naturally what were the triggers that would polarize the innate immune cells? So I looked really early on in this mice and what I found was that the very first event was leaks of blood-brain barrier. It was opening of the blood-brain barrier in this mouse before inflammation, before demyelination, before neuronal loss. And this is really what shaped the question that, is it possible that these blood leaks that happened very early in the pathology, could this be the instigators of pathogenic inflammation in the brain?Eric Topol (03:34):Yeah. So in a way, you got at this question because of the chicken-and-egg and what happens first, and you got to the temporal saying, which happened first as you said, the leak before you could see evidence of inflammation and being able to study this of course in the experimental model, which you couldn't really do in people. And what I love about the description of your career, which has been quite extraordinary contributions is connecting the dots between the blood, the inflammatory response and the brain. Perhaps no one has done that like you have. And before we get into the recent paper, a lot of people are not aware that a year ago, a group in the UK known as PHOSP-COVID, they published a really important paper in Nature Medicine of over 1,800 people who were hospitalized with Covid and they found that fibrinogen was the best marker for cognitive deficits at 6 and 12 months (Figure below)(04:40):So that's just one of many papers, but it's a particularly well done study that already before you got into this work that recently published had emphasized fibrinogen. And by the way, again, having spent a lot of years in clots in the arteries, for me, we have to just get it down to fibrinogen plus thrombin gets you to fibrin. Okay, so fibrin is a major player here when fibrinogen is cleaved. So here we have the basis that you established, which is the fibrinogen leakage into the brain, activating inflammation, activating microglia, which like the macrophages of the brain and inciting the whole process. And before we close, I want to not just talk about Covid, but Alzheimer's too. But now let's get into the study that you did, [Fibrin drives thromboinflammation and neuropathology in COVID-19] which is striking, I mean really striking. And can you kind of take us through, because you not only demonstrated the importance of fibrin in inciting neuroinflammation in this model, but also how you could reverse it or prevent it. So this, and you looked at it in many different ways, this was a systematic approach. Maybe you can take us through how you were able to make such compelling evidence.The Multimodal EvidenceKaterina Akassoglou (06:09):Yes, thank you. First of all, thank you for bringing up the human relevance because this was also our inspiration for the work that we did in the Covid study. So as you mentioned in Covid patients, fibrinogen unbiased mass spec analysis was identified as the predictive biomarker for cognitive impairment in Long Covid patients. And this was in addition to also neuropathology data about the abundance of fibrin deposition in the brain. And these were studies that were done by NIH that have found deposition of fibrin in the brain and the reports for the abnormal and puzzling coagulation in Covid that is not setting other infections and also in many cases not always relating with the severity of symptoms. So even mild cases of Covid also had increased coagulation. I was really intrigued by this human, all this evidence in human data, and I thought that maybe the way that we're thinking about this, that it's systemic inflammation that drives the clotting.(07:24):Maybe there's another aspect to this. Maybe there is a direct effect of the virus with the coagulation cascade, and in this way maybe this can be an instigator of inflammation. So this was the original idea to be able to reconcile this data from the clinic about why do we have this prevalence of coagulopathy in Covid. And of course, the second question is, could this also be a driver of the disease? And of course, we're in a unique position because we have been studying this pathway now for over 20 years to have all the toolbox, the genetic toolbox, the pharmacologic toolbox to be able to actually really address these questions with genetic loss of function studies, with a blood innate immunity multiomics pipeline that we have set up in the lab. And of course, with preclinical pharmacology in our ABSL3 facility. So we had the infrastructure in place and the source in place to actually really dissect this question with both genetic tools as well as also technology platforms.Eric Topol (08:29):And you had in vivo imaging, you're the director of in vivo imaging for Gladstone and UCSF. So you do have the tools to do this.Katerina Akassoglou (08:38):Yes. The imaging that you mentioned is really important because this is, we employed that very early in our studies over now 15 years ago. And the reason was sometimes from snapshots of histopathology, you cannot really understand the sequence of events. So by being able to image these processes, both neuronal activity, microglia activation, infiltration of peripheral cells in the brain, this is how we could see the steps that what happens early on and to be able to answer these chicken-and-egg questions that you mentioned. So these were very, they're very important experiments, especially at the beginning because they were hypothesis driving and we were able to ask the right questions to drive our research program.Eric Topol (09:26):Now was the binding of the spike protein to one key site in fibrinogen, was that known before? [See outstanding Figure below from Trends in Immunology]Katerina Akassoglou (09:36):No, this was not known. So there was evidence that there are abnormal clots in Covid, but it was not known whether the spike protein would directly bind to protein to the coagulation cascade. So one of the key discoveries in our study was to use peptide array mapping and be able to identify not only the binding, but exactly the domains on fibrin that spike binds too. And what we found was two key domains, one the inflammatory domain and the other the plasmin binding site, which is important for fibrin degradation. So this suggested a potential dual deleterious role for this interaction, both by maybe affecting inflammation, but also delaying fibrinolysis, which is the degradation of this toxic protein from the brain. And indeed, we found that this interaction was responsible for all these two aspects, including decreased degradation, more inflammation, but also at the same time increased, increased coagulation. So it was a really pathogenic interaction.Eric Topol (10:47):Yeah, actually it's pretty striking. You have these two sites, the plasmin cleavage site of fibrinogen, which as you say, we knew there was a problem with clots. We knew that, but we didn't know exactly the spike protein how exactly it was implicated, particularly with fibrinogen. And then this other site, the CD11b-C18, now that's fancy for surface receptors of macrophages. And basically, this is critical because it's this microglia activation in the brain, and I know you saw it in the lungs as well through this other site that spike protein activated. So you had a twofer here of things that you discovered that the SARS-CoV-2 spike protein was capable of doing. This was a really big revelation. And then you also looked at mice that were genetically manipulated. So maybe you can, because before we get to your antibody monoclonal, the ways that you proved this were, I mean, one thing after another is really systematic. So maybe you can teach us about that.Thanks for reading Ground Truths! This post is public so feel free to share it.Establishing CausalityKaterina Akassoglou (12:08):Yeah, sure. So the first was about chemistry experiment. So this of course, we had to get to the next step to see is there any causality for this pathway. So we employed genetic loss of function studies and we had knockout mice, either fibrinogen knockout mice, this mice have all blood proteins except fibrinogen, and they have a delay in coagulation so they don't clot properly. But we also had a mutant mouse, which is a fibrinogen NK mouse. And this was a mutation only within this inflammatory domain that you mentioned, inflammatory domain that binds to C11b-C18. Other names for this is of course complement receptor 3, Mac-1 (αMβ2). It's the same, many names for this receptor, that as you mentioned, is expressed not only in microglial in the brain, but also peripheral immune cells including macrophages as well as also neutrophils which are CD11b expressing.(13:12):So we now have genetic models to be able to look at both complete depletion of fibrinogen, but also a very specific mutation and very selective mutation that only blocks the inflammatory properties without affecting the properties of fibrin in hemostasis. And these mice were made many years ago by a very close collaborator, Jay Degen at the University of Cincinnati. So what we found is that when we block either the inflammatory domain or we completely deplete fibrinogen, there was this profound protection after infection in internasal infection with the virus in lung inflammation. And this was both suppression of oxidative stress and this pathogenic inflammation in the lung, but also decreasing fibrosis, which has been associated with also Long Covid. And the surprise came from the transcriptomic data. So when we did transcriptomic analysis in this mice in the lungs, we found perhaps the expected decrease in the immune signatures in macrophages. This was in line with our previous work in, as you mentioned, Alzheimer's models, multiple sclerosis models. But what also was really surprising is there was that genes that are associated with activation of NK cells were upregulated. And of course this was the first time we had infected these mice, previously we had not done an infection before. So I think that maybe because of this region we had not seen before in our data this immunomodulatory role of fibrin that not only surprises the macrophage response, but also increases these NK cells that are important for viral clearance.Eric Topol (15:00):So again, the finding another important unique finding is the natural killer (NK) cells and effect there from the activation of this, as you said, the inflammation site or the CD11b-C18 that we've been talking about. So now another layer of this, a dimension of your Nature paper was that you tested an antibody that you already had developed so-called 5B8. A monoclonal that specifically binds to the domain of the one we're talking about this inflammation domain of fibrinogen. So can you tell us about what that showed?Katerina Akassoglou (15:45):Yes, so we tested this antibody in different models of Covid, which were both models with neuroinvasion and models without neuroinvasion. So we used both transgenic mice for hACE2, the human ACE2 infected with Delta, but we also use mouse adapted viruses like Beta that is just in the wild type mice with no transgenic being involved that these are without neuroinvasion. And we wanted to see if the antibody had any potential protective effects. And what we found is that the antibody protected from inflammation in the lung. So the data looked so similar with a genetic mutation of this pathway, protection from inflammation, decreased fibrosis, increased viral clearance, so decreased spike and viral proteins in the lungs. But we also found a protection in the brain. So the brains of this mice, including both the models we used with neuroinvasion and without, they both have had microglia activation in the brain. And we also found neuronal loss in the Delta infected mice and the antibody protected from both neuroinflammation but also improved neuronal survival in the mice. Showing that there can be this despite regardless of which model we used, there was this protective effect suggesting that by blocking fibrin, either the periphery or in the brain, this could be protected for these models.Eric Topol (17:28):Yeah, so I mean this is fascinating because until now, until this report of yours and your colleagues at Gladstone, there was knowledge that there would be neuroinflammation from Covid, both in patients from various biomarkers and imaging as well as in experimental model. But what this did was take it to the fibrin story, and I guess that's one of the questions you nailed that how important fibrin is, but that doesn't necessarily rule out other triggers of neuroinflammation, right?Katerina Akassoglou (18:04):Oh, absolutely not. So I think that this is one of the mechanisms that can be very important, especially in some patients. But we know that there are additional of course mechanisms of neuroinflammation including auto-antibody responses, as well as also endotheliopathy that are persistent endotheliopathy, this can be interacting also with each other. So I think that it's important for future research that we understand how do these mechanisms feed into each other? Are there a positive feedback loops between autoimmune mechanisms and coagulopathy and endothelial dysfunction with inflammation? But I think most importantly, I think that if we're thinking of this in the context of patients, can we identify patients with mechanism that might be more prevalent in specific cases of Long Covid and tailor our potential future clinical trials towards the needs of Long Covid patients?Towards TreatmentEric Topol (19:06):Absolutely. I did interview some months back on Grounds Truths, Michelle Monje at Stanford, who I'm sure and interact with, and she's also works not so much on the fibrin side, but on neuroinflammation and the likeness between this condition in people and chemo brain because of the inflammation that's seen there. So we've talked about the multiple triggers that could contribute to brain inflammation, which I think most people would say in Long Covid this is one of the most, besides obviously the lack of energy, the profound fatigue and disability, but the cognitive function hit, not just brain fog is often profound. And we've just seen some reports about that, and particularly in hospitalized patients, how bad that can be. So that gets us to a potential treatment. Now, one of the things that's out there dangling, there's many things that people have talked about in terms of why can't we have a treatment for Long Covid?(20:13):And now of course this fibrin pathway, if you will, lends itself to many possibilities, whether it's anticoagulants or fibrinolytics like a tPA or things like nattokinase, which is a Japanese food enzyme that you could get at the nutrition centers or whatever. What are your thoughts? Because we don't have any good studies. There are all these little, tiny studies and they don't provide much conclusion, and you have an antibody that could potentially be effective. As I understand it, you set up a company some years ago, Therini Bio and used to be called MedaRed. You're the first woman scientist at Gladstone to develop a spin out company, which is another point of congratulations on that. But could the antibody be tested in patients or what do you think about these other possibilities?Katerina Akassoglou (21:15):Yes, yes. These are great questions. So first of all, the different approaches that you mentioned have very different mechanism of action. So degrading fibrin, the degradation products of fibrin also can have deleterious effects. The dimer, for example, can be very pro-inflammatory. So at the same time, blocking coagulation can also have a diverse effects because this can lead to excessive hemorrhage. So the approach that we took was to selectively block the inflammatory properties of fibrin without affecting beneficial effects of the molecule in normal hemostasis. So the challenge when I made the antibody was to be able to dissect these two functions of fibrin. It's our most important clotting factor, but at the same time, a molecule with profound pro-inflammatory capacity. So the observation that these two domains, the clotting domain and inflammatory domain were not overlapping, was really the foundation of this invention was that we could maybe create this antibody to be able to target them in a selective way.Other Neurologic Conditions (22:31):So the antibody I developed is neutralizing blood toxicity by blocking the inflammatory domain of fibrin without adverse coagulation effects. And it's now completing phase one trials. So it has already completed the single ascending dose at 40 milligram per kilogram. It's interim data were announced already for this trial, with no safety signals. So if the antibody completes this year, the phase one trials, then it should be possible to be tested in different patient populations. You mentioned before chemo brain, and I think it's important that we think that blood-brain barrier disruption occurs among many neurological conditions, and it's an early event associated with early disease onset and worse prognosis in multiple sclerosis, Alzheimer's disease, traumatic injuries. So I think that it's by developing a strategy, therapeutic strategy to neutralize blood toxicity, this can have applications in a wide range of neurological conditions with vascular dysfunction.Eric Topol (23:54):Yeah, no. In your Nature Immunology 2020 piece [Figure below], you started with the 1883 identification of multiple sclerosis (MS) lesions were “engorged with blood”, the first link between blood leaks and brain inflammation. So this has enormous potential. And what I like about this Katerina is that you've dissected the clot component versus the inflammatory trigger of the fibrinogen and fibrin story. And this is so vital because if you keep throwing these things that just going to work on the clot and not deal with the pro-inflammatory consequences, then you're going to get the wrong impression that clots are not that important. And by the way, you did mention, and I want to come back to that too, endothelial inflammation, which is another feature of Long Covid is another kind of interactive part of this because when the lining of the blood vessel is inflamed, it will attract microthrombi and also be a participant in this whole affair. What do you think about Alzheimer's and the prospects of being able to interfere with Alzheimer's? We have 20 years in someone before this process takes hold and meets clinical manifestations. Would an antibody like this ever be useful along the way?Katerina Akassoglou (25:29):Yeah, so well, our antibody was tested first in Alzheimer's, this models when it was originally published, and we performed reversal trials in Alzheimer's models. So we dosed mice when they have established amyloid plaques, microglia activation, neuronal loss, and we could reverse this effect so it could increase cholinergic neurons in mice, reduce inflammation in a very selective way, only the neurotoxic part of inflammation and for genetic depletion of this pathway with akin mice in Alzheimer's disease. Also, improves from cognitive impairment, and we now have a new paper in Cell Press that is showing this effects also with really nice and unbiased machine learning models for behavioral segmentation [Figure below].So I think that there is the data both from genetic studies and the antibody show projection in Alzheimer's disease. And of course, as you might have read the recent Lancet report from the Lancet committee on dementia that identified the vascular risk factors as the key contributors, especially post sporadic cases of Alzheimer's disease that is over 90% of Alzheimer's disease that is not genetically linked.(26:58):So I think that there is a real need in Alzheimer's disease to be able to block this vascular induced pathology. And an antibody like the fibrin neutralizing therapy could be positioned to be protective from the vascular induced immune-mediated neurodegeneration in this disease as well. I mean, ultimately, I think that we need to be thinking the terms of efficacy. So we want to have a drug that is efficacious, but we also want it to be selective. And the selectivity is really important because the immune system has so many protective functions. So if we block phagocytosis, we end up with more debris, decrease of neurorepair, anti-myelination. So by blocking a ligand here and not blocking, not eliminating a cell type or blocking a global pathway in this cell, but biologic a single ligand, I think we have been able to achieve this balance between efficacy, but also safety because we only block this neurotoxic populations and not the entire innate immune response that also has been beneficial for metastatic functions in the brain.Blocking NeuroinflammationEric Topol (28:19):So you're bringing up another critical concept about targeting the inflammation, this kind of goldilocks story of how much you interfere with the immune response and how much you are able to reduce the adverse pro-inflammatory effects. So that gets me to what if we don't know in any given patient how much fibrin is having a role in their Long Covid. Although we know it has to be a prominent feature because we saw it in, not just a hospitalized patient series that I mentioned we reviewed, but other papers as well. But what about if you just try to take on inflammation like through a GLP-1 drug or cGAS–STING or any of these really strong anti-inflammatory pathways. Do you see a difference in a generalized approach versus a specific approach that is really fibrin centered?Katerina Akassoglou (29:22):Yeah, so we have a focus actually on both because we wanted to dissect the downstream intracellular pathways of fibrin, and it's interesting that we can find specific inflammatory mediators that potentially can also be targeted as well, to be able to preserve that specificity, which I think is really important because if we don't preserve the specificity, we'll end up with a lot of adverse effects by eliminating major immune responses. But the point that you raised I think is really important because it's not enough to have an efficacious and selective drug if you don't know the patient population that will benefit from this drug. So I think that in addition to the drug discovery studies, it's important to develop also biomarker programs with both fluid biomarkers, but also imaging biomarkers to be able to identify the patient populations that will benefit from such treatment.(30:25):So if for example, a patient population has a fibrin deposition, blocking only downstream might not be enough, and it might be really important to neutralize this fibrin toxicity in the brain of patients. And with our target engagement studies, we show that at least in animal models, the antibody can be there. So I'm very encouraged by also programs that are going on now in the scientific community to develop noninvasive ligands to be able to image fibrin in the brain that are already tested in different patient populations like multiple sclerosis. Because I think we're going to learn so much from the biology as we start interrogating and asking these questions now in different patient populations.Eric Topol (31:14):I think that's a vital point you're making because the success of a clinical trial here in a clinical syndrome that is mosaic with lots of different types of pathways. If you can nail down the patients that would have the most to stand to benefit from a particular intervention, that the chance of you not missing the benefit that is matching the marker, what image marker or other markers is so vital. Well, we've talked, I think, about some fascinating discoveries that you and your colleagues have made. I mean, it's really extraordinary, and obviously we need this in Long Covid. But you know what, Katerina, it's almost made me think that you were warming up to this for three decades, that somehow or other you were working on all this stuff and then came Covid. Is that how you see it, that somehow or other you didn't know that all the work you were doing was going to wind up in this space?Katerina Akassoglou (32:18):Oh, I never thought I would work in a virology project. This collaboration started over Zoom with Warner Greene. We were both sheltering in place. It was the beginning of the pandemic, and the first reports were coming out about this puzzling coagulopathy. And our labs were hardly operational at the time, as you know, we had to close down our labs for a while. And however, this was a very big problem, and we thought that this is our role as scientists. If we feel that we can contribute and we have the tools to contribute, we felt that it's important that we pivot some part of our research, and even we wouldn't be doing this before, but it was important to pivot a part of our research and collaborate. And I think studies like this, this study would have been impossible without a team of collaborators. As you know, there were over 50 scientists involved at Gladstone, UCSF, UCLA, UCSD, Stanford University. Without collaboration, this study wouldn't be possible. So I'm really grateful to everyone who came together to solve this problem because I think that's what scientists should be doing. We should be solving problems as they arise.Eric Topol (33:41):Well, and also, I think a lot of people don't realize that, for example, when the Covid vaccines came along, people think, oh, well, it all got done in 10 months since the sequence of the virus, when in fact it took 30 years at least between all the factors that went into having an mRNA and sequencing virus and nanoparticles. And in many ways, your arc of this work is like that because it took three decades to have all the tools and the basic understanding, the antibody that you had developed for different reasons and this fascinating unraveling of what's going on in the model and undoubtedly in some patients at least as well. So before we wrap up, have I missed anything about this just remarkable work you've done?Katerina Akassoglou (34:33):Oh, thank you. I just want to thank you for this discussion and thank you for emphasizing the different areas and the different decisions that this pathway can have implications both for our understanding, our basic understanding of the blood brain immune interface, as well as also potential translation. And I think that the curiosity sometimes of how things work, I never thought it would work on Covid, like you mentioned at the beginning, but I think that basic science and curiosity driven science can sometimes lead to discoveries with translational implications that hopefully might benefit patients one day.Eric Topol (35:21):Yeah, well, undoubtedly it will. We're indebted to you, Katerina and all the folks that you have teamed up with, connecting the dots at the neurovascular interface. Phenomenal work and will follow the subsequent with great interest and it will likely not just a story about Long Covid, but other areas as well, so thank you.*********************************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly help fund our summer internship programs.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don’t want to bother you with an email for content that you’re not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe