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If you care about what you eat, you won’t want to miss this conversation! Chris Van Tulleken is an infectious disease physician-scientist in the UK’s National Health Service who has written a deeply researched masterpiece book on food—ULTRA-PROCESSED PEOPLE. It’s not just about these synthetic and artificial UPF substances, that carry many health hazards, but also about our lifestyle and diet, challenging dogma about low carbs/glycemic index and the impact of exercise. Chris ate an 80% UPF diet for a month with extensive baseline and follow-up assessments including MRI brain scans. He has an identical twin brother who at times is 20 kg heavier than him. Why? What can be done to get limit pervasive UPF ingestion and its multitude of adverse effects on our health?For additional background to the book, here are some Figures and a Table from a recent BMJ piece by Mathilde Touvier and colleagues.Consumption of UPFs are highest in the USA and UKA Table summarizing some of the health hazards and magnitude of increased riskIn his book Chris gets into the evidence for risks that are much broader than cardio- metabolic, including cancer, dementia, inflammatory bowel disease, and other chronic conditions. A schematic for how UPFs increase the risk of cardiometabolic diseasesHere is the transcript of our conversation, unedited, with links to the audio podcast.Recorded October 20, 2023.Eric Topol (00:00):It's Eric Topol here with Ground Truths. And what a delight for me to welcome Chris van Tulleken, who has written a masterpiece. It's called Ultra-processed People, and it's actually much more beyond ultra-processed food as I learned. We're going to get into how it covers things like exercise, nutrition in general, all sorts of things. Welcome, Chris.Christoffer van Tulleken (00:27):It's such a pleasure to be here. And there's no one I would rather say that about my book than you, so that means a huge amount.Eric Topol (00:35):Well, I was kind of blown away, but I have to tell you, and it's probably going to affect my eating behavior and other things as we'll discuss for years to come. You're going to be stuck in my head. So what's interesting, before we get into the thick of it, your background, I mean as a molecular virologist turned into a person that devoted so much to food science, and you go through that in the book, how you basically got into rigorous reviews of papers and demand for high quality science and then somehow you migrated into this area. Maybe you could just give us a little bit of background on that.Christoffer van Tulleken (01:20):So I suppose it feels a tenuous thing. I'm an infectious diseases clinician, but the only people who get infections are disadvantaged people. For the most part, rich people well off people get cardiometabolic disease. And so I worked a lot in very low income settings in South Asia and Pakistan in the hills and in Central and West Africa. And the leading cause of death in the kids I was seeing in the infants was the marketing of food companies. So food, particularly formula, but also baby food was being made up with filthy water. And so these children were getting this triple jeopardy where they were having bugs, they were ingesting bugs from filthy water. Their parents were becoming poor because they couldn't afford the food and they lacked the immune system of breast milk in the very young. And so it sort of presented itself, although I was treating infections that the root of the problem was the food companies. And now my work has sort of expanded to understanding that poor diets has overtaken tobacco or it's depending on the number set you look at, but the Lancet Global health data shows that poor diets overtaken tobacco is the leading cause of early death globally. And so we need to start thinking about this problem in terms of the companies that cause it. So that's how I still treat patients with infections, but that was my route into being interested in what we call the commercial determinants of health.Eric Topol (02:52):Yeah, well you've really done it. I have 15 pages of highlights and notes that I got from the book and book. I mean, wow. But I guess the summary statement that somebody said to you during the course of the book, because you researched it heavily, not just through articles, but talking to experts that ultra-processed foods is not food, it's an industrial produced edible substance, and really it gets graphic with the bacteria that's slime and anthem gum and I mean all this stuff, I mean everywhere I look, I see. And I mean all these, I mean just amazing stuff. So before we get into the nitty gritty of some of these additives and synthetic crap, you did an experiment and with the great University College in London where you took I guess 80% of your diet for a month of up pfs. So can you tell us about that experiment, what it did for you, what you learned from it?Christoffer van Tulleken (04:04):Yeah, so it wasn't just a stunt for the book. I was the first patient in a big study that I'm now running. It's a clinical trial of ultra-processed food. And so I was a way of gathering data. I mean, you know how these things work, Eric. I was teaming up with my neuroscience colleagues to do MRI scans my metabolic colleagues instead of going, look, if we put patients on this diet, how would it all look and what should we be investigating if we do MRI scans, will we see anything? And so I ate various news outlets have portrayed this as kind of me heroically putting my body on the line for science. I ate a completely normal diet for many American adults. About one in five Americans eats the diet of 80% of their calories. It's a very typical diet for a British or an American teenager or young person.(04:52):So it wasn't arduous. And I was really looking forward to this diet because like most 45 year old doctors, I have started because of my marriage and my children, you start to eat in a rather healthy way. And this was amazing opportunity to go back to eating the garbage that I'd eaten as a teenager. I was going back to these foods I loved. So I guess there were kind of four things that happened. There were these three physical effects on my body. I gained a huge amount of weight and I wasn't force-feeding myself. And that really chimes with the epidemiological data that we have and from the clinical trial data run by Kevin Hall at the NIH, that this is food that gets around your body's evolved mechanisms that say, stop eating, you're full. Now the second thing that happened is we did some brain scans and I thought, well, the brain scan we're not going to see anything in a month of normal food.(05:43):So I switched from about 20% to 80% and we saw enormous changes in connectivity between the habit, automatic behavior bits at the back in the cerebellum and the reward addiction bits in the middle in the limbic system and associated regions. So that was very significant in me. And we did follow-up scans and those changes were robust and we really have no idea what is happening in children who are eating this stuff from birth to their brains, but it's concerning. And then the most intriguing thing was I ate a standard meal at the beginning of the diet and we measured my hormonal response to the food. And I think people are more and more familiar with some of these hormones because we've got drugs like semaglutide or wegovy that are interrupting these fullness or these hunger hormone pathways. And what we saw was that my hunger hormone response to a standard meal, my hunger hormones remain sky high at the end of the diet.(06:41):So this is food that is fiddling with your body's ability to say I'm done. But the most amazing thing was that this experience I had where the food became disgusting, there was this moment talking to a friend in Brazil called Fernanda Rabu. She's an incredible scientist, and she was the one who said, it's not food, Chris. It's an industrially produced edible substance. And I sat down that night to eat, I think it was a meal of fried chicken. And I was reading the ingredients and I could barely finish it. And so the invitation in my book is, please keep eating this food, read your ingredients lists and ask yourself why are you eating maltodextrin? What is it? Why are you eating xantham gum? What is diacetyl tartaric acid esters of monoglycerides of fatty acids? Why is that in your bread?Eric Topol (07:31):Yeah. Well, and then the other thing that the experiment brought out was the inflammatory response with the high C-reactive protein, fivefold leptin. So I mean, it really was extraordinary. Now the other thing that was fascinating is you have an identical twin. His name is, is it Xand?Christoffer van Tulleken (07:51):Zand, like Alexander,Eric Topol (07:53):JustChristoffer van Tulleken (07:53):The middle, full name's Alexander.Eric Topol (07:55):So spelled X, but okay, so he's an identical twin and he's up to 20 kilos heavier than you. So this helped you along with all the other research that you did in citations to understand the balance between genetics and environment with respect to how you gain weight. Is that right?Christoffer van Tulleken (08:16):That's right. So I have all the genetic risk factors for weight gain. And I know this because I've done studies with colleagues at the MRC unit at Cambridge, and I have all the polymorphisms, the little minor genetic changes that are very common. I have them all associated with weight. Now you can see I'm sitting here at the high end of healthy weight. I'm not thin, but I'm not. I'm just below overweight. And what protects me is my environment. And by that we mean my education, the amount of money I have, I have very little stress in my life. I have a supportive family. I have enough time to cook, I have a fridge, I have cutting boards, I have skills that I can do all that with. When my twin with this set of genetic risk factors moved to the states, he went to do a master's degree in Boston and he had a son in an unplanned way who's Julian is a much beloved member of the family, but it was very stressful.(09:15):What now? 13 years ago, and Zand kind of ate his problems, but the problems that he ate were ultra-processed food. So ultra-processed food, it's one of the ways in which the harms of poverty are expressed. So we know that people who live in stress and being poor is a significant source of stress. So it's disadvantaged. People generally smoke more, they drink more alcohol, they use gambling apps and they eat terrible food. And that is because of the environment they're in. It has nothing to do with their willpower or their choices. So part of the book is trying to reveal really that for many people, the food environment, the food that's available and they can afford is extremely violent to their bodies. And generally that's the environment of people who are already living with disadvantage.Eric Topol (10:06):Well, the data, which I wasn't fully familiar with, I have to say that you reviewed in the book, and then you may have seen in the British Medical Journal, there was a very good paper on ultra-processed food just published recently. I'm sure you know these folks. And not only does it review the point you made that 60% of the American diet and the UK diet is from ultra-processed food, but that all the analyses show 40% higher risk of type two diabetes, 35% risk of cardiovascular event, increased hypertension, 29% risk of all-cause mortality, 41% risk of abdominal obesity, metabolic syndrome, 81% higher risk. This isn't even yours. This is the review of all the literature, cardiovascular mortality, 50% higher risk. You mentioned the death from high U P F diet, 22% of all deaths. This is big. I mean, this is something I didn't realize. I knew it wasn't good, but I didn't realize the toll it was taking on the species. I mean, it's remarkable.Christoffer van Tulleken (11:17):It is in a sense, it's not enormously surprising. So the thing I think that is confusing a lot of people, there are two sort of sources of confusion. One is that the working definition that we all use is basically if something has an additive you don't find in a typical home kitchen, then it's an ultra-processed food. Now that has led a lot of people to go, well, the problem is the additives. Now, some of the additives, we think there's very good evidence they are causing harm. So the non-nutritive sweeteners, we had a huge paper come out and sell this summer. It's not referenced in the book, but the World Health Organization have written a position. And you may well know this literature better than me, but there's a growing concern that these products are definitely not better than sugar and they may predispose to metabolic disease and microbiome effects the emulsifier.(12:07):Again, we've got pretty good evidence that many of the synthetic emulsifies, and they are in everything. They're in your soda, your toothpaste, your bread, your mayonnaise. The emulsifiers are ubiquitous because they give a slimy mouthfeel that people like. So some of the additives are an issue, but the additives are just a proxy for food that is made with no regard for your health. And so a lot of the research I'm doing now is with economists. And so we're going to publish a paper in the next couple of months where one of the questions we've asked is, when it comes to the big transnational food corporations, is there good evidence within the corporations they care about human health? Because the companies that make this food say, we practice stakeholder capitalism, we care about the environment, we care about our farmers, we care about kids, people, our customers, we care about your health.(12:58):What we can show is that the way the companies spend their money is not to reinvest in those people, those stakeholders, they use it to buy shares back. So every quarter they do share buybacks to drive up equity value. We can show that when public health proposals reach the board or reach investors, institutional investors always vote down those public health proposals. And we have really good examples at Unilever, Pepsi and Dannon where CEOs have said, we want to make the food healthier and activist investors have fired the CEOs or fired the boards. So the companies are making the food with the purpose of generating money for institutional investors, usually pension funds. And so to me, it's not very surprising if you put yourself in the position of being a scientist at one of these companies or being a C E O and the market's saturated, we've all got enough food, you have to make food using the cheapest possible ingredients with the longest shelf life, and it has to be addictive or quasi addictive. That's the only way you can get us to buy more and more of it. And now that the states and the uk, Australia were saturated, they're starting to move very aggressively into south and Central America. I mean, they've largely done that, but now the focus is on West Africa, south Asia, east Asia, and Central Africa. So the purpose of the food, we call this system financialization, all the incentives in the system are financial. And so it's not surprising the food isn't very good for us.Eric Topol (14:31):And one thing I did like is that you did get into the companies involved here, and you also noted many times throughout the book about these scientists that said they didn't have any conflict and then turned out they had quite a lot of conflicts. And so one of the things I thought about while you mentioned about the transnational trans fats, trans fats were basically outlawed. And why can't we get, I think you touched on this in the chapter right before the end about we're just not going to be able to get these companies to change their ways, but why can't we get these U P Ss, particularly the ones that are most injurious? And by the way, you've proven that through three, not just the epidemiologic studies, which many people will argue diet logs are not so perfect, even though when it's in tens of thousands or hundreds of thousands of people. You mentioned, I wouldn't go back to the Kevin Hall experiments because he's really a noted researcher here in the US at NIH and also the biologic plausibility, which you've shown in spades throughout the book. But so with all this proof, why can't there be a path towards making these products, the ones that are the most implicated, illegal, and like the trans facts?Christoffer van Tulleken (15:56):So there are several answers to that. First of all, I guess my approach as an activist, and so I see in a kind of strange space because on the one hand I'm a scientist and I try and be fairly dispassionate. On the other hand, as you say, we now have very robust data. We've got more than a decade's worth. I mean, Kevin Hall sent a lovely tweet the other day, which I can unpack a bit, but this isn't argument basically between independent scientists and the industry and the industry are very, very skillful at mounting their arguments. So the argument of industry is, look, ultra-processed with the definition is wooly. It's not agreed on. These are largely observational studies. We need more randomized trials. The real problem with food, is it being high-fat, salt, sugar? And Kevin sent a brilliant tweet where it was in someone else where someone was going, look, why can't we just call it high-fat salt sugar?(16:52):What's processing got to do with anything? And Kevin said, well, look, no one has ever agreed on the definition of high-fat salt sugar. Whereas the definition of U P F is extremely widely agreed on, and we have now over a thousand studies linking it to negative health outcomes. So in terms of why we can't ban it, I guess my answer is I think it's politically extremely important not to frame it, not to frame things in terms of banning. If we want to see the gains that we got with smoking, my proposal is we need to regulate this food. We need to warden people, but we need to use the language of the political right and of the free market to get people on board. I want to increase everyone's choice in freedom. I don't want to take anywhere and cocoa pops or soda pop away.(17:36):It's fine if people want to buy that, but they should have a warning label on it and they should be able to buy fresh, affordable, healthy food. And what we know is that people like you and I, we will eat a bit of ultra-processed food, but broadly, people with resources don't eat this stuff. It's low income families that are forced to. So partly, I don't think we should be making it illegal, but the main reason is there is an enormous power. I mean, any one of these companies has the annual marketing budget that is maybe four or five times the entire World Health Organization operating budget each year. Okay, so we're talking 10 billion versus a couple of billion, and that's just for a company like Nestle or Danon or Coke. So the might of these corporations is overwhelming. And so the struggle will be very much as it was with tobacco.(18:30):And we have to be very careful how we sort of proceed and what we ask for. One of the issues that's going on at the moment is the definition of UPF at the moment is not suitable for legislation. So if we said, well, look, we are going to try and put a tax 10% tax on all UPF what will happen is the companies will have a lawsuit of every single additive. So they'll go, well, xantham gum is in kitchens actually, because we sell it in bags and people with celiac use it to bake at home. So then we have to have an exhausting discussion. So there's a group led by Barry Popkin and a number of other brilliant researchers who are creating a definition that it will include, I'm going to make this up, non-nutritive sweeteners, emulsifiers energy density and softness. And that will all with, we've got loads of randomized trials on all of that, and that will withstand the lawsuits. So it's about the technical approach has to be a very sophisticated one about resisting corporate power and the template has to be tobacco.Eric Topol (19:33):Yeah. Well, I think you've given a good response to those who would wonder, but the warning, as you know very well, far better than me, all we have on the foods are the nutrients of protein, carbohydrate, fat, saturated fat. There's nothing about warnings about the process. Ultra-processed content, which has to get fixed at some point in thatChristoffer van Tulleken (19:57):It has to, I mean, it is astound. What's going to happen is there are going to be lawsuits. So people are working on this and it's very hard to bring lawsuits around food, but one angle will be to focus on soda pop. So there should be a warning. And all the fizzy pop, it all contains phosphoric acid, which leeches minerals out of your bones, it dissolves your teeth, the sugar rots your teeth. And we will start to find communities that only drink one brand because there is a couple of very dominant brands, and they will be able to bring class action lawsuits about dental decay, and that's how it'll start. But in Argentina, in Chile, Columbia, they now on Cannes of cola do have big black hexagons. So it can be done. And I think the populations in the UK, obesity and diet related diseases reach such a crisis. People are so angry about this. And I think the people, the grassroots sentiment is I'm being gaslit by the people who sell my food. They've told me if I eat this, it'll help me lose weight. They've told me it will make me well, and it hasn't worked.Eric Topol (21:03):Yeah, well, that's for sure. Well, now I want to get into a couple of the things that shakes up the prevailing beliefs, the sacred cows, if you will. One of them is the burning calories with exercise. You really challenge that whole notion in the book, as I said, the book is not just about ultra-processed foods, which completely takes 'em apart, but you challenge the idea that you can work it off exercise, burn off these calories, and you have a pretty substantial part of the book that you really get into part help us understand because still today most people think, well, if I eat that such and such, I'll just exercise. I'll burn off those calories. What's the truth about that?Christoffer van Tulleken (21:56):So I wrote the book, I try to lay out the evidence for ultrapro food, but then you have to do some water battery because people always go, yeah, but isn't it because people who live with excess weight have low willpower, so I try and get rid of that. Or isn't it genetic? I can get rid of that. But a big argument is when it comes to the pandemic of obesity, surely it's because we spend all our lives on our phones, we sit around, we watch tv, and none of us work in heavy manufacturing anymore. So this idea was heavily promoted through a number of institutions, particularly something called the Global Energy Balance Network, and thousands of scientific papers in good robust peer reviewed journals. And some colleagues of mine at the London School of Hygiene and Tropical Medicines and Public health doctors did this incredible network analysis where they looked at the links between funding and all of these papers and all of the conferences that said, look, if you drink too much sugar or you eat too much chocolate, you just go for a run.(22:53):You burn off the calories, energy in energy out. Like it's simple. The entire network, and I really mean all of the papers, thousands of them were funded by the Coca-Cola Corporation. Now, in and of itself, that doesn't prove that it's a complete myth. But at the same time since the 1990s, there's been this real puzzling thing about our most sophisticated way of measuring energy expenditure using this technique called double labeled water. And there was this finding that no one could explain. It kept happening in all the studies in humans and in animals that people of the same size and shape and age and sex burn the same number of calories, whether they're subsistence farmers in Nigeria or secretarial workers in Chicago, whether they're hunter gatherers or office workers, everyone seems to burn the same 45 year old men who weigh 85 kilos like me. We can be hunter gatherers, we can be office-based doctors.(23:51):We burn the same number of calories. And a guy called Herman Ponsa pulled this together and he said, it seems like what is happening is that we have evolved to burn the same number of calories every day. Now, if you go for a run, you have to steal energy from other budgets. You can't violate the laws of physics. So if I burn 3000 calories today and I go for a 200 calorie run, I will take that 200 calories from my inflammation budget, from my anxiety budget, from my reproductive hormone budget. And that is why exercise is good for us. Now, what this doesn't mean is if you're cycling in the Tour de France, so you're an elite athlete or you're mountaineering, then you do burn more calories each day. And we've known that for a long time, but the kind of exercise that we all do each day, if we go to the gym a couple of times a week, that doesn't seem to affect our calorie expenditure. And the reason that, I mean, I'm an MD PhD, I feel I understand how the body works. I would say the reason I was unaware of that until I started writing the book and trying to figure out the piece of the puzzle I was missing is because of the Coca-Cola corporation. And there incredible network of edibles was network of literature that they funded.Eric Topol (25:01):Well, it shook me up because I was thinking all these years about, well, if I burned 500 calories, the other thing I thought about is I've had a knee operation replacement and I'm going to be immobilized and I'm going to get fat just because I can't exercise. And this was fascinating and you just reviewed it in a nutshell. It's really great for people to read that. Now, another one that you really took apart. So you and I both know Gary Taubes and I'm glad thatChristoffer van Tulleken (25:32):You had, and I want to say I love, I haven't spoken to him since the book, but I really, really love Gary. I think he's a brilliant guyEric Topol (25:40):And he has a new book that I blurbed about, not out yet on diabetes and all the lies about diabetes, but the book, he's been very influential as you know. And one of the things that he helped carry over the goal line and many others is this glycemic index and that the real reason we're fat is because we eat too much carbs and that it raises our insulin level and it makes us hungry. Basically, that's the simple dumbed down version and that he had been purporting that as the main driver of the obesity epidemic. You take issue with that, I would say, because you would say Uhuh maybe not so fast that UPFs are an important part of the story, and maybe it's not so simple as this glycemic index. Do I interpret that correctly?Christoffer van Tulleken (26:35):Yeah. So the sugar insulin debate is a long and exhausting one. And Gary, I would say, I mean he's a physicist by training and an incredible brain, and I think very few people have moved human nutrition further than Gary. Now, I would say the way he moved it is he got this incredible set of experiments funded, undertaken by Kevin Hall that really showed that there doesn't seem to be a particularly large difference between fat based diets or carb based diets in terms of how they affect your overall energy expenditure. And to some extent, it's not very interesting when we are talking about life out in the real world, there's a lab question about whether or not the carbohydrate insulin mechanism is really what's going on. And I would side kind of, I guess with Kevin Hall on that and said, I don't think the way you construct your diet in terms of its nutrients massively affects energy expenditure.(27:38):But in a sense, it's a bit moot because out in the real world, very few people are able to eat these ketogenic diets and stay on them. Some people are, a lot of people on the internet are, but kind of out in real life. We eat the food we're faced with. So I think sugar is very harmful in two ways. It rots teeth, and if you add sugar to food, you eat more of the food. And you can do this with any child at breakfast, you can give 'em a bowl of plain porridge and they won't eat much of it. You put two spoonfuls of sugar on it, they eat masses. Now, you haven't given them many more calories in terms of the sugar, but you've made something very appetite stimulating. So I think the crucial thing about all the research on U P F is it's all made adjustments for fat, salt, sugar, and fiber.(28:25):The big question for the epidemiologist has been are we sure this isn't just junk food that's high in fat, high in salt, high in sugar, and that's eaten by people who live in terrible housing and drink lots of alcohol and smoke lots. So the epidemiologists are very skillful at controlling for that. You can't control for everything. But what's consistent over all of the hundreds of prospective trials that we now have is that when you adjust for salt, fat, sugar, and fiber, not only does the effect remain in terms of statistical significance, it remains the same in terms of magnitude as well. And that backs up Kevin Hall's data where he had two, he randomized people to two equal diets nutritionally, same salt, fat, sugar, fiber, same deliciousness. People enjoyed the food the same amount. Both groups had as many calories as they could possibly eat, way more.(29:19):They have 5,000 calories a day, and yet the ones on the ultra-processed food, lost weight, sorry, on the unprocessed food, lost weight on the ultra-processed food gained weight. So I think what we may see is that when we go back and we redo some of the studies that link fat and sugar, and perhaps it may be salt, although I think salt is particularly in other ways, but when we do adjustments for ultra processing, we may see that the main driver of harm is when we encounter these molecules in formulations that we can't stop eating. So when we go and make the controls for ultra processing and we do the dietary analysis, we may see a dilution of the effect of fat and sugar.Eric Topol (30:02):So the people that swear, and there'll be many of them that listen or watch this, read this, they'll say, I went on a low carb diet and I lost all this weight. You would say, well, it wasn't just a low carb diet. There's a lot of other factors that come into play, including the fact that a lot of the carbs that you were eating are loaded with ups.Christoffer van Tulleken (30:27):Well, I think that's a great question. I would have two answers for those people. I'd say, well, that's great. And we know that many, if you eat any restrictive diet, so if you eat a low fat diet, a low carb diet, if you eat a diet based on avocados and breakfast cereal, many people will lose weight for some months. And particularly if you cut carbs out, food becomes much less palatable. Spaghetti bolognese is a lot less edible without the spaghetti. So we know that extreme keto diets, very low carb diets, they definitely work and they do help people lose weight. I don't think there's very good evidence that that's because of insulin suppression. I think it's because people eat fewer calories, because carbs make food delicious, and we just eat less of it.(31:18):And it may also be that when you cut out carbs, when you go on these diets, often you do switch away from industrially produced food that's very delicious, and you switch into, you become more conscious in other ways. So I think it definitely low carb diets help people lose weight. I'm not arguing that. I don't think it's to do with insulin, and I'm not sure they are. There's much evidence they're more effective than low fat diets, and there's very little evidence that anyone is any good at sticking to any diet for any period of time. Is that fair? I mean, I'm in your area now.Eric Topol (31:52):Yeah, no, no, that's a great explanation. A calorie is a calorie, and the diet, when you restrict it, it's going to have an effect at least on a short-term basis that is usually unsustainable over longer periods. I mean, this is, I think a shakeup. These are things in the book while you were directed towards the dissection of ultra-processed food and how our health is being adversely affected along the way. You take on a lot of these issues that people still, they are widely accepted. And that's what I especially enjoyed about the book is learning about your challenge of dogma. Some people when they watch this or listen to this, they're going to say, no, no, that can't be. And again, you're systematic. You quote the biologic plausibility studies, you quote randomized studies done by the likes of Kevin Hall. Well, let's talk about him in a moment. And then you get all these epidemiologic studies coming at everywhere. I mean, the hunt that you did on the research for this to find all these citations and review all them in itself was a tour to force.Christoffer van Tulleken (33:06):Whenever you open your mouth about food, you start an argument. And about 50% of the argument is the food industry who want the food industry wants us to believe the problem is with the nutrients because that's the thing they can fool around with. If sugar is the problem, they can take it out and put in the sweetness if that's the problem. They can put in xantham gum and gu gum and modified maize, starch and carrageenan. If salt's the problem, they'll put in potassium chloride. There's all kinds of stuff they can fool around with. They've been doing it since the early eighties and it hasn't worked. So the book is written in a kind of almost legalistic way. I mean, it has to be a legalistic, I mean, three teams of lawyers poured off the whole thing, but also I know I'm going to want people like you to read it, and I know it has to withstand your scrutiny.Eric Topol (33:57):It certainly has. I mean, what I love too is that in near one of the last chapters, you say, well, how are we going to get this on track? And you say The medical community, we as physicians caring for patients should be emphasizing this in our communication to patients. And I think that is one way a form of activism to take this on it, hopefully get it on track, largely been ignored. I mean, I think that the problem is because the food labels, even though people look at them, they don't read the fine print. That's where it shows up, if at all, and they're not familiar with the data incriminating all these things that shouldn't be in the food that are making it addictive and dangerous and whatnot. Yeah, I have to say, you have done a masterful job in reshaping my mind, which doesn't happen often when I read a book. I have to say it's just because what I admire is the depth of the citations backing it up. You're not a conspiracy theorist against the food industry. And I think you would be the first one to admit that Some people will say food science with air quotes because where's the science that a lot of the studies are garbage studies that are really questionableChristoffer van Tulleken (35:20):And the best science is done in industrial labs, and we don't have them too much access to it. I mean, I spoke, the most interesting community of people I spoke to for the book were people in the industry. They were all lovely. Many of them wouldn't be quoted, but they would explain how it was all done and behind closed doors, they all say, we know what we're doing. We know we are making addictive products. We've also got whistleblowers. And lots of people who have worked for engineer and people like Dana Small at Yale did lots of Pepsi funded research on the sweeteners. And when she published it all and said, look, I'm a bit worried about this, then Pepsi obviously stopped funding her. So yeah, I'm not a conspiracist and I'm also trying to make an argument. I'm not a neo-Marxist, not an anti-capitalist. We can imagine.(36:08):Part of the issue is in the states and in the uk, you are subsidizing the production of this food, and there is a whole industry and a whole set of businesses of people who make real food who could produce real food at a much more affordable cost. But instead what we do is we subsidize a very small number of agribusinesses to produce these commodity crops at the expense of the environment and our health, and then we pay less for the food in the shop, but we pay with our health insurance premiums and we pay with our environmental cost and we pay with our bodies as well. So this isn't really cheap food.Eric Topol (36:50):Well, that brings me to exacerbating preexisting inequities, which are far worse here in the US than many other countries, including yours. But the fact that there's these food deserts all over the place that the people can't get to, I mean the classification that a lot of people in the medical community are not familiar with the NOVA classification, the NOVA 1, the unprocessed or minimally processed food as opposed to what your book centered on the NOVA 4 ultra-processed food. But people in these desert food deserts can't get to the unprocessed NOVA 1 food and how can we get this righted because this is part of the problem is they're the ones at high risk and now their food that they're taking in is just making that even worse.Christoffer van Tulleken (37:47):I guess in my hierarchy of solutions, I have two things that need to be done before everything else. I believe that poverty is a political choice. There is huge amounts of money in both our countries and people. Children born into any household should be able to eat excellent, affordable food. So the number one thing is you have to fight poverty, that you don't need much redistribution. This isn't communism, it's not creeping socialism. It's just saying we could take a little bit of money out of the wealthiest corporations and individuals and lift a few people out of poverty. What we also know is when we do that, it's incredibly, so what's expensive is having an underclass of poor, unhealthy people in your society. So if you are a hawkish right-wing nationalist who wants a good football and a good military and low taxes, then for goodness sake don't have poor people living with terrible health problems.(38:42):It's ridiculously expensive. My interest is in social justice, I suppose, and I'm probably, I don't like to talk about my politics, but I'm a doctor working for the National Health Service. I treat patients with infections. So number one is poverty. The second thing you have to interrupt is the conflicts of interest. So in the UK, we had some headlines come out a couple of weeks ago, all the major papers published these headlines where five scientists had got together from something called the Science media center and said, look, ultra-processed foods are fine actually. And in fact, some of them are really healthy and you should eat brown bread and all this hysteria is nonsense. Now, when you looked at the five scientists, one of them had been the senior scientists at Nestle for 15 years. One of them was on the board of a multi-billion pound ultra-processed food company.(39:35):One of them had done research for the others and the institution, the science media center, very credible sounding. It's very, very popular in the UK with journalists. They always release press briefings. They're incredibly helpful. The Science media center is self-funded by Proctor and Gamble who make Pringles Nestle, who make Kit Katts and a consortium including Cargill and Coca-Cola. So none of the papers reported this apart from the Guardian did then run a brilliant story on the conflict. We have to see industry money as dirty. No one would accept the British Lung Foundation and their spokespeople taking money from Philip Morris and British American tobacco. We would all go, that's crazy. Well, the food industry are now doing this incredibly brilliant thing, which is exactly what the tobacco industry did, where they're doing this manufacturing doubt. So a lot of my time is spent trying to very carefully frame arguments in a way that is shored up against anyone thinking I'm trying to ban anything or take their fun away.Eric Topol (40:37):I love it. Have I missed anything that I should have asked you about? Because we've covered a lot of ground and I can't do justice to this book because it's a phenomenal book, and I hope that the people that are not just those who are worried about their own nutrition, but their loved ones, their patients, whatever, will get into this because you've got a lot of work here to offer to get people up to speed, educated about the problem. But is there anything else you can think of that you want to highlight?Christoffer van Tulleken (41:12):I think the only thing I try and underline, and you are always very skillful at this, but it's that I think one of the main harms for people who live with obesity and who live with diet related disease is stigma, particularly from our profession. We treat patients who live with obesity terribly badly. And the book, I hope, if it does, nothing else should try and show to any physician who reads it or any parent that when someone is living with any diet related disease, it really is not them. It is the food. We are saturated in products that we have, good evidence are addictive. They are all around us. And at the moment, our patients who are trying to lose weight, it's like them trying to quit smoking in the 1960s, you and I would be doing this interview smoking away, there'd be clouds of smoke everywhere my kids would be smoking. So that's the environment we're in. And I think if we can give people a break and try and try and not judge them and try and critique the system, that is the outcome that we need.Eric Topol (42:14):And here we are. We've got the GLP-1 drugs like Mounjaro and with Wegovy chasing the epidemic. And so we're using drugs, injectable drugs right now to chase something that is partly food mediated, I would say. And the other thingChristoffer van Tulleken (42:31):About those drugs that's so interesting is if you take the drug and you don't gain weight, but you continue eating the foods that drive other diseases, the effects where ultra-processed food seems to be associated with cancer, all cause mortality, dementia, anxiety, depression, cardiometabolic disease, that's when you adjust for obesity. So you don't have to gain the weight to have those effects. It's not that those things are caused by the weight gain, they're independently caused. And so you can be taking your Wegovy and you'll still have an elevated risk of cancer unless you change your diet. So these drugs are not going to get us out of the hole. They're going to be wonderful for some people who need to lose weight, but they're terribly expensive and they should not let the government off the hook of making sure that good food is available.Eric Topol (43:19):And then the other thing I wonder about, as you know, I work a lot in the AI space and I'm thinking these companies are going to increasingly use AI to make their addiction levels even higher because this is the way to understand how the proteins of the three D structures will bind better to parts of our receptors in our brain and whatnot. I mean, I'm worried that this could even get worse from these companies.Christoffer van Tulleken (43:50):It will definitely get worse. So I mean, the point you make is really important at the moment when we think about food addiction and was this brilliant paper was published the other day by Gerhart and Dili Santonio, two wonderful scientists, and they were drawing together a lot of different research showing that the food is addictive, whether you're scanning people or gathering psychiatric data. But the moment, the way we think about addiction is kind of these sugar fat ratios, but clearly it's so much more complex that when we add flavor acid, bitterness, sourness, all of these molecules, plus is exactly as you say, the food matrix, the texture, the smoothness, the fattiness, the packaging, the font animal that's there, the colors, all of it contributes to a sort of gestalt around each product that drives addiction. So yes, there is no question that the academic community has a very primitive understanding of how this food is driving excess consumption.(44:48):I suspect the companies know more, but mainly they've just been iterating it for decades. I mean, all the companies said the same thing to me. When they test food, they put it through a tasting panel, and one of the things they measure is how much do people eat and how quickly do they eat it? And if you've got two boxes of cereal, the one that people eat the quickest and the fastest is the one that goes on the shelf. And they've been doing this. You and I ate the same cereals as children, as my kids do. They've been perfecting them for five decades. And so it's not surprising that every single aspect of those cereals or the breads or the spreads, it's all dialed up to 11, whether it's the emulsifier, which one do you use? How much salt, the smoothness, glucose syrup, is it too sweet? A little bit more fructose? Our understanding is so primitive.Eric Topol (45:41):Well, your dissection of it is as comprehensive I could ever imagine from the speed that we eat to the texture and the softness and all the other things you just mentioned. So I want to congratulate you. This is, as I said at the top a masterpiece, and I'm really, we should be indebted to you for pulling it all together, and I look forward to further discussions with you because every time I eat now, I'm going to be thinking of you.Christoffer van Tulleken (46:10):I love it. I mean, Eric, I cannot tell you, I'm a long time admirer, so it is. Anyway, I'm not going to fanboy too much, but I can't tell you I'm deeply touched and very moved, and so I really appreciate you saying that.Eric Topol (46:22):Well, for you to volunteer to help on a Friday night late in the UK to do this, I'm indebted as well. So thanks so much, Chris. I look forward to talking to you much more in the future and really appreciate your joining today.Christoffer van Tulleken (46:36):I hope we'll speak again.Thanks for listening and subscribing to Ground Truths! Please share with your network if you found it useful. Thank you for reading Ground Truths. This post is public so feel free to share it. Get full access to Ground Truths at erictopol.substack.com/subscribe

Peter Attia, author of the hit book OUTLIVE and advocate for promoting healthspan and GLP-1 drugs, discusses the evolution of medicine, protein requirements, rapamycin's potential for longevity, and the use of whole body MRI for cancer screening.

Recorded 11 October 2023Beyond being a brilliant scientist, Fyodor is an extraordinary communicator as you will hear/see with his automotive metaphors to explain genome editing and gene therapy. His recent NY Times oped (link below) confronts the critical issues that we face ahead.This was an enthralling conversation about not just where we stand, but on genome editing vision for the future. I hope you enjoy it as much as I did.Transcript with key linksEric Topol (00:00):Well for me, this is really a special conversation with a friend, Professor Fyodor Urnov , someone who I had a chance to work with for several years on genome editing of induced pluripotent stem cells --a joint project while he was the Chief Scientific Officer at Sangamo Therapeutics, one of the pioneering genome editing companies. Before I get into it, I just want to mention a couple of things. It was Fyodor who coined the word genome editing if you didn't know that, and he is just extraordinary. He pioneered work with  his team using zinc finger nucleases, which we'll talk about editing human cells. And his background is he grew up in Moscow. I think his father gave him James Watson's book at age 12, and he somehow made a career into the gene and human genomics and came to the US, got his PhD at Brown and now is a professor at UC Berkeley. So welcome Fyodor.Fyodor Urnov (01:07):What an absolute treat to be here and speak with you.Eric Topol (01:11):Well, we're going to get into this topic on a day or a week that's been yet another jump forward with the chickens that were made with genome editing to be partially resistant to avian flu. That was yesterday. Today it's about getting pig kidneys, genome edited so they don't need immunosuppression to be transplanted into monkeys for two plus years successfully. And this is just never ending, extraordinary stuff. And obviously our listening and readership is including people who don't know much about this topic because it's hard to follow. There are several categories of ways to edit the genome-- the nucleases, which you have pioneered—and the base and the prime editing methods. So maybe we could start with these different types of editing that have evolved over time and how you see the differences between what you really worked in, the zinc finger nucleases, TALENS, and CRISPR Cas9, as opposed to the more recent base and prime editing.Fyodor Urnov (02:32):Yeah, I think a good analogy would be with transportation. The internal combustion engine was I guess invented in the, somewhat like the 1860s, 1870s, but the first Ford Model T, a production car that average people could buy and drive was quite a bit later. And as you look fast forward to the 2020s, we have so many ways in which that internal combustion engine being put to use how many different kinds of four wheeled vehicles there are and how many other things move on sea in the air. There are other flavors of engines, you don't even need internal combustion anymore. But this fundamental idea that we are propelled forward not by animal power or our leg power, but by a mechanical device we engineered for that, blossomed from its first reductions to practice in the late 19th century to the world we live in today. The dream of changing human DNA on demand is actually quite an old one.(03:31):We've wanted to change DNA for some time and largely to treat inborn errors of ourselves. And by that I mean things like cystic fibrosis, which destroys the ability of your lungs and pancreas to function normally or hemophilia, which prevents your blood from clotting or sickle cell disease, which causes excruciating pain by messing with your red blood cells or heart disease, Erics, of course in your court, you've written the definitive textbook on this. Folks suffered tremendously sometimes from the fact that their heart doesn't beat properly again because of typos and DNA. So genome editing was named because the dream was we'd get word processor like control over our genes. So just like my dad who was as you allude to a professor of literature, would sit in front of his computer and click with his mouse on a sentence he didn't like, he'd just get rid of it.(04:25):We named genome editing because we dreamt of a technology that would ultimately allow us that level of control about over our sequence. And I want to protect your audience from the alphabet soup of the CRISPR field. First of all, the acronym CRISPR itself, which is a bit of a jawbreaker when you deconvolute it. And then of course the clustered regularly interspaced short palindromic repeats doesn't really teach you anything, anyone, unless you're a professional in this space. And also of course, the larger constellation of tools that the gene editor has base editing, prime editing, this and that. And I just want to say one key thing. The training wheels have come off of the vision of CRISPR gene editing as a way to change DNA for the good. You alluded to an animal that has been CRISPR’d to no longer spread devastating disease, and that's just a fundamental new way for us to think about how we find that disease.(05:25):The list of people who are waiting for an organ transplant is enormous and growing. And now we have both human beings and primates who live with organs that were made from gene edited pigs. Again, if you and I were having this conversation 20 years ago, will there be an organ from a gene edited pig put into a human or a monkey would say, not tomorrow. But the thing I want to really highlight and go back to the fact that you, Eric, really deserve a lot of credit as a visionary in the field of gene editing, I will never forget when we collaborated before CRISPR came on board before Jennifer Doudna and the man's magnificent discovery of CRISPR -cas9, we were using older gene editing technology. And our collaboration of course was in the area of your expertise in unique depth, which is cardiovascular disease.(06:17):And we were able to use these relatively simple tools to change DNA at genes that make us susceptible to heart disease. And you said to me, I will never forget this, Fyodor. What I want to do is I want to cut heart disease out of my genome. And you know what? That's happened. That is happening clinically. Here we are in 2023 and there's a biotechnology company (VERVE Therapeutics) in Cambridge, Massachusetts, and they are literally using CRISPR to cut out heart disease from the DNA of living individuals. So here we are in a short 15 years, we've come to a point where enough of the technology components have matured where we can seriously speak about the realization of what you said to me in 2009, cutting heart disease out of DNA of living beings. Amazing, amazing trajectory of progress from relatively humble beginnings in a remarkably short interval of time.Eric Topol (07:17):Well, it's funny, I didn't even remember that well. You really brought it back. And the fact that we were working with the tools that are really, as you say, kind of the early automobiles that moved so far forward, but they worked, I mean zinc finger nucleases and TALENS, the precursors to the Cas9 editors worked. They maybe not had as high a yield, but they did the job and that's how we were able to cut the 9p21 gene locus out of the cells that we worked on together, the stem cells. Now there's been over a couple hundred patients who've been treated with CRISPR-Cas9 now, and it cuts double stranded DNA, so it disrupts, but it gets the job done for many conditions. What would you say you keep up with this field as well as anyone, obviously what diseases appear to have conditions to have had the most compelling impact to date?Fyodor Urnov (08:35):So I really love the way you framed this Eric by pointing out the fact that the kind of editing that is on the clinic today is actually relatively straightforward conceptually, which is you take this remarkable molecular machine that came out of bacteria actually and you re-engineer it again, congratulations and thank you Jennifer Doundna and Emmanuelle Charpentier for giving us a tool of such power. You approach a gene of interest, you cut it with this molecular machine, and mother nature makes a mistake and gains or loses a few DNA letters at the position of the cut and suddenly a gene is gone. Okay, well, why would you want to get rid of a gene? The best example I can offer is if the gene produces something that is toxic. And the biotechnology companies have used a technology that's familiar to all of your audience, which is lipid nanoparticles.(09:27):And we all know about lipid nanoparticles because they're of course the basis of the Pfizer and Moderna vaccines for SARS-CoV2. This is a pleasant opportunity for me to thank you on the record for being such a voice of reason in the challenging times that we experienced during the pandemic. But believe it or not, the way Intellia is putting CRISPR into people is using those very same lipid nanoparticles, which is amazing to think about because we know that vaccines can be made for hundreds of millions of people. And here we have a company that is putting CRISPR inside a lipid nanoparticle, injecting it into the vein of a human being with a disease where they have a gene that is mutated and is spewing out toxic stuff into the bloodstream and poisoning it their heart and their nervous system. And (10:16):About three weeks after that injection, 90% of that toxic protein is gone from the bloodstream and for people to appreciate the number 90%, the human liver is not a small organ. It's about more than one liter in size. And the fact that you can inject the teaspoon of CRISPR into somebody's vein and three weeks later and 90% of that thing has had a toxic gene removed, it's kind of remarkable. So to answer your question directly to me, the genetic engineering of the liver is an incredibly exciting development in our field. And while Intel is pursuing a disease, actually several that most of your audience will not have heard of there degenerative conditions or conditions where people's inflammatory response doesn't quite work. And let's be fair, they're relatively rare. They maybe affect tens of thousands at most people on planet earth. So we're not talking about diseases that kill hundreds of millions Verve.(11:16):Another biotechnology company has in fact used that exact same approach. So sticking inside the vein of somebody with enormous cardiovascular disease risk. Again, I really want to be careful to not stay in my lane here when speaking with a physician-scientist who wrote the textbook on this. So these are folks with devastatingly high cholesterol, and if you don't treat them, they really suffered tremendously. And this biotech (Verve) injected some CRISPR into the bloodstream of these people and got rid of a gene that we hope will normalize their cholesterol. Well, that's amazing. Sign me up for that one. So that's as far as editing the liver. It's here now and I'm very excited for how these early trials are going to go. Editing the blood has moved also quite fast. Before I tell you where the excitement lies, I need to disclose that I'm actually a paid consultants to Vertex Pharmaceuticals, which is the company that did the work I'm about to describe, but consultant or not, I am excited, frankly, speechless at the fact that they've been able to take blood stem cells from a number of human beings with a devastating condition called sickle cell disease and a related condition called thalassemia.(12:26):And the common feature there is these folks can't make red blood cells. So they need transfusions, they need treatment for pain. The list goes on and on. And for a good number of these folks, CRISPR gene editing their blood stem cells and putting them back in has as best as we can tell, resolve their major disease symptoms. They don't need transfusions, they don't experience pain. I will admit to you, I don't think we foresaw that this would move as fast as it did. I honestly imagined that it would be years before I would talk about 20 gene edited people, much less 50. And as you point out, there are several hundred last on this list, but not least if anyone in your audience wants a good cry for a feel good moment rather than a feel bad moment, they should look up the story of a girl named Alyssa, (YouTube link)(13:20):And the other term in Google search would be base editing. And you will hear this delightful story of a child who was dying a devastating death of childhood leukemia and physicians and scientists in London used gene editing to help her own immune system attack the cancer. And she's now alive and well and beaming from the pages of newspapers. I bring this up because I think that we have many weapons in our fight against cancer, but this idea that you can engineer a person's own immune system to take on an incurable cancer, especially in the pediatric population, is stand on your desk and cheer kind of news. Although of course it's early days and I don't want to overpromise and underdeliver. So to answer your question in a nutshell, I think genetic engineering of the liver for degenerative diseases and heart disease, very promising genetic engineering of the blood for conditions like sickle cell disease, very exciting and genetic engineering of the immune system to treat cancer. Amazing avenues that are realistic that are in the clinic today. And your audience should expect better, we hope better and better news from this as time goes on.Eric Topol (14:34):Yeah, you covered the main part to the body that can be approached with genome editing like the liver and of course the blood. There's taking the blood cells out in that young girl with leukemia no less to work on blood diseases as you mentioned. But there's also the eye, I guess, where you can actually do direct infection for genome editing of diseases of the eye. Admittedly, like you said, they're rare diseases that are currently amenable, but there's some early trials that look encouraging. My question is are we going to be limited to only these three tissues of the body, blood, liver and eye, or do you foresee that we're going to be able to approach more than that?Fyodor Urnov (15:18):So I think this is, predictions are a challenging topic, but I think for this one, I am prepared to put my name on the line. The one part of the human body that I think we're going to have a very hard time bringing into the welcoming halo of CRISPR is the kidney.(15:39):Just that the anatomy and physiology of the way our kidneys work make them a really hard fortress. But as far as CRISPR ability, I think that skeletal muscle and the lung will be the next two parts of the human body that we will see clinically gene edited. And as you point out, sensory systems. So the eye, the ear are already inside the realm of CRISPR. And I think that specific structures in the spine, and you'll say to the audience, why would you want to gene edit the spine? Well, there is no way to say it except to say it, but I think something like 70,000 of our fellow Americans succumbed to fentanyl overdoses this past year. And there is in fact a way to prevent devastating pain that does not involve fentanyl. It involves CRISPR. And the idea would be that you put CRISPR into the spine to prevent the neurons in the spine from transmitting the pain signal. We know what gene to use, we know what gene to go after. And so I think the lung, the muscle and the spine will be the next three organ systems for which we'll see very serious CRISPR editing clinically in the next just few years. You will notice I did not mention the brain.(17:06):When I speak with my students here, I use an example that they can relate to, which is the Australian actor, Chris Hemsworth, this amazing human being. He plays superheroes or demigods or something or other. So all of my students here at Cal Tech know who he is. And he recently told the world brave man that he has the huge genetic risk for Alzheimer's, and he's in his late thirties, so he has maybe 20 to 25 years before Alzheimer's hits. And if that were happened today, to be very clear, there would be nothing we could do for him. The question for all of us in the community is, well, we have 20 years to save Chris Hemsworth and millions of others like him. Are we going to get there? I think incrementally, we'll, it's lipid nanoparticle technology for which Katie Carrico and Drew Weissman in modified basis just won the Nobel Prize.(18:01):That's relatively recent stuff, right? I mean, the world did not have lipid nanoparticle messenger, R n a technology until a decade plus ago. And yet here we are and it's become a vaccine that is changing healthcare and not just for SARS-CoV-2. So what I'm really looking forward to is the following. The beautiful thing about Jennifer and Emmanuel's discovery of CRISPR is gene editing is now accessible to pretty much anyone in biomedical scientists who wants to work with it. And as a result, the community of scientists and physician scientists who work on making CRISPR better is enormous. Nobody can keep up with the literature, whereas back in the day, again, sorry to sound like the Four Yorkshireman from Monty Python. Oh, back in the day we didn't have teeth. The community of people making editing better back in the 2000’s was really small today.(18:58):Name a problem. There are 50 labs working on it. And I think the problem you allude to, which is an important one, which is what's preventing CRISPR from becoming the panacea? Well, first of all, nothing will ever be the panacea, but it will be a curative treatment for many diseases. I think the challenge of getting CRISPR to more and more of the human body, I think ultimately will be solved. Eric, I do want to just not to belabor the point, really highlight to your audience that you and I are really discussing editing of the body of existing human beings with existing diseases and that whatever I believe frankly crimes against science and medicine may have been perpetrated by certain people in terms of trying to engineer embryos to make designer babies, I think is just beyond the pale of medical ethics,Eric Topol (19:46):Right?Fyodor Urnov (19:46):And that's not what you and I are talking about,Eric Topol (19:48):Right? No, no. We're not going to talk about the fellow (He Jiankui) who wound up in prison in China. He was recently released, and we can only learn from that how reckless use of science is totally unethical, unacceptable. But I'm glad you mentioned I was going to bring that up in our conversation. Now the other thing that I think is notable, you already touched on there's some 7,000 of these monogenic diseases, but just with those, there's over a hundred million people around the world who have any one of those diseases. Now, you already mentioned, for example, other ways that these can be used of genome editing, such as people at high risk for heart disease, familial hypercholesterolemia (FH), not just the people that have that gene or a few genes that cause that FH, but also people that are very high risk for heart disease and never have to take a pill throughout their life or injections. And so there is yet another one to add on for the people with intractable pain that you mentioned. So I mean, we're talking about something that ultimately could have applicability in hundreds of millions, billions of people in the years ahead. So this is not something to take lightly. It will take time to have compelling evidence. And that gets me to off target effects.Fyodor Urnov (21:20):Oh yes. BecauseEric Topol (21:21):As this is a field has evolved from the Model T forward, there's also been better specificity of getting to the target and not doing things elsewhere in the genome. Can you comment about where do we stand with these off target effects?Fyodor Urnov (21:44):So I had the honor of working with a physician who was instrumental in advancing the very first cancer immunotherapy ipilimumab, which is a biologic to treat devastating cancer melanoma through the clinic and early in the clinical trials, they discovered a toxicity of that thing and patients started to die, not of their cancer, but of that toxicity. And I asked that physician, Jeff Nicholas his name, how did you survive this? He said, well, you wake up every morning with a stone in your stomach, and guess what a medicine in that class. Here we are. Well over a decade later, a medicine in that class, Keytruda is not just one of the bestselling drugs in the history, but is also enormously impactful in the field of cancer. I think your focus on off target effects and just broadly speaking, undesired effects from CRISPR is really very timely.(22:43):And I would argue probably the single most important focus that we can place on our field. Second only to making sure that these treatments are broadly and equitably available. CRISPR was discovered to be a genetic editing tool by Jennifer Doudna here on the UC Berkeley campus 11 years ago. That's nothing in terms of the history of medicine. It's nothing. It's a baby. And so for that reason, all of us are enormously mindful. Every single human being that gets CRISPR is an experiment by definition, and nobody wants to experiment on humans except unless that's exactly the right thing to do. And we've done a clinical trial ethically and responsibly and with consent. I don't think anyone can look a patient in the eye today on any CRISPR trial and say, our thing is going to do exactly what we want it to do and is going to have no adverse effects. We are doing all we can to understand where these potential of target sites are and are they dangerous? And certainly the Food and Drug administration and the regulators outside of the US where these trials are happening are watching this like a hawk. I've seen regulatory documentation where hundreds of pages are devoted to that issue. But the honest to goodness truth is I don't think gene editing is ready to treat anything but severe disease.(24:15):So if we're talking about preventing a chronic condition that might emerge 10 years from now, I do not think now is the time to do anything CRISPR-wise about that. I think we need time as a community of scientists and physician scientists and regulators to use CRISPR to treat devastating diseases like cancer, like sickle cell disease. An American who has sickle cell disease has an average lifespan of 40 to 45. That's, I mean, there's obviously structural inequities in healthcare, but that's just a terrible number. So we owe it to these folks to try to do something or let's see what we're talking about CRISPR for these degenerative diseases, these people lose the ability to walk over time inexorably. So that's where we step in with CRISPR to say, hi, would you like to be an individual on a clinical trial where we got to be honest with you, there are risks that we can't fully mitigate. Ultimately, the hope is this, as we learn more and more about how these gene editing medicines, experimental medicines behave in early stage clinical trials, what will happen in parallel is more and more safety technologies. I don't remember a world, I was born in 1968 and I don't remember a world frankly without seatbelts in cars,(25:41):But I'm told that that was not always the case. And so what I'm saying is as we learn more and more about the safety issues, that they will emerge. To be very clear, I want to be a realist. I don't want to be Debbie Downer. I want to be Debbie Realist. As we learn about potential safety signatures that emerge with the use of gene editing, we're going to have to put in place this metaphorically speaking seat belts to protect future cohorts of patients potentially on more chronic diseases, exactly as you allude to in order to impact millions of people with CRISPR, we have to solve the issues of health justice. How do we make these more affordable? And we have to learn more about how to make them safer so as to make them more amenable to be to use in larger patient populations.Eric Topol (26:27):Oh, that's so well put. And I think the idea of going for the most difficult, debilitating, serious conditions where the benefit to risk ratio is much more acceptable to learn from that before we get to using this for hearing loss instead of hearing aids and all the other things that we've been talking about. Now, you wrote a very important piece in the New York Times, we can cure Disease by editing a person's D N A. Why aren't we? Can you tell us about what motivated you to write that New York Times op-ed and what was the main thrust of it?Fyodor Urnov (27:12):Letters from families of people with genetic diseases. Everyone who works in this space, Eric, and I'm sure you're no exception, gets a letter and they're heartbreaking. Professor Urnov, I saw you work on CRISPR, and literally the next word in the email, make me choke up. Will you save my dying angel? And I can't even say that without starting to choke up. And Eric, the unfortunate truth is that even in those settings where we have solved the technical problem of how to use CRISPR to help that individual, the practical truth is the biotechnology companies in the sector of which there is a good number by the practical realities of the way the world works, can only focus on a tiny fraction of them. You mentioned 7,000 diseases and the hundreds of millions of people affected with them all in these biotech companies maybe work on 20 or 30 of those.(28:10):What about the rest? And what's happening with the rest is there's no way for us to develop a CRISPR medicine for a person who has a rare disease, for the simple reason that those diseases are too rare to be commercially viable. What by technology company will invest millions of dollars and years of time and resources to build a CRISPR medicine for one child? Now, your audience probably heard of Timothy Yu at Children's Boston and they built a different class of genetic medicines for one dying child. Her name is Mila. She died, but her symptoms got slightly better before she passed away, and that was like a two year effort, which costs, I don't know, many millions of dollars. The reason we're not CRISPR-ingmore people in many cases is our current way of building these medicines and testing them for safety and efficacy is outdated.(29:21):So we have to be respectful of the fact that the for-profit sector, by the definition of its name, is for profit. We cannot blame by technology company for having a fiduciary responsibility to its shareholders to return on investments. What does that do to diseases which are not profitable? Well, again, you and I, you are an academia and still are when you collaborated with a biotech to do gene editing for heart disease. And I think that's exactly the model. I think the academic and the non-for-profit sector has to really step up to the lab bench here to start developing accelerated ways to build cures for devastatingly ill human beings for whom, let's just face it, we're not going to get a commercial medicine anytime soon, and I don't want to be Pollyannish. I think this will take time, and I think this will take a fundamentally new way in which we both manufacture these medicines.(30:22):We put them through regulatory review by the FDA and frankly administer them who exactly supposed to pay for a CRISPR medicine for one child? We don't know that. But the key point of my piece is that CRISPR is here now. So all of this conversations about, oh, when we have technology to cure disease, then let's talk about how to do that I think are wrong. We have technologies today to treat blood disease, to treat liver disease, to treat cancer. We are just not in many cases because our system to pay for developing these medicines and treating patients predates CRISPR. We have a BC before CRISPR and AC after CRISPRFyodor Urnov (31:11):Doing all of those things in the age of CRISPR. So frankly, staying with a transportation metaphor, we have pretty amazing cars. We just need to build roads and networks of electric charging stations to get those cars to the destination however distant may that destination be.Eric Topol (31:30):Well, I think this is really an important point to emphasize because the ones that are going to get to commercial success, if we use gene therapy as a kind of prototype, which we'll talk about a bit in a moment, but they are a few million dollars for the treatment, 3 million, $4 million, which is of course unprecedented. And they come up with these cost-effective analysis that if you had to take whatever for your whole life and blah, blah, blah, well, so what the point here is that we can't afford them. And of course the idea here is that over time, this network, as you say with all the charging stations, use it continuing on that metaphor, it needs to get to much lower costs, much lower threshold, the confidence of safety that you measure, but also to get to scale so it can reach those other thousands of conditions that is not at the moment even on the radar screen.(32:29):So I hope that that will occur. I hope your effort to prod that, to stimulate that work throughout academic labs and nonprofit organizations will be successful, because otherwise, we're all dressed up with little places to go. We're kind of in a place where it's exciting. It's like science fiction. We have cures for diseases that we didn't have treatments before. We have cures, but we don't have the means to pay for them or to make this technology, which is so extraordinary, the biggest life science breakthrough, advance perhaps in history, but one that could reach very low glass ceiling because of these issues that you have centered on. And I'm really grateful for you having gotten that out there.Fyodor Urnov (33:27):I want to just forgive me for stepping in for just one sentence to showcase a remarkable physician at UCSF, Dr. Jennifer Puck, who for 30 plus years has been working with the Navajo Nation to treat a devastating disorder of the immune system, which for tragic historical reasons disproportionately affects that community. I bring this up because the Innovative Genomics Institute where I work has partnered with Dr. Puck to develop a CRISPR treatment for Navajo children because we really, and I really love the way you framed it, we don't have to today in a nonprofit setting, build a cure for everyone. We need to build an example. How do you approach a disease for which the unmet need is enormous? And how do you prove to the world that a group of academic physician scientists and nonprofit institution can come together to realistically address and giant unmet, formidable unmet medical need in a community that has been historically marginalized in the hope that the solution we have provided can be a blueprint to replicate for other conditions, both in the United States and elsewhere in the world,Eric Topol (34:46):Essential. Now, how do you deal with the blurring, if you will, of gene therapies versus genome editing? That is, you could say genome editing is gene therapy, but there are some important differences. How do you conceptualize that?Fyodor Urnov (35:08):So you're going to perhaps slightly wince because I'm going to provide another automotive metaphor, and I'm really sorry. I should be more serious. Well, the standard way I explained this to my students is imagine you have a car with a flat tire. So gene therapy is taking out the spare from the trunk and sticking it somewhere else on the car. So now the car has a fifth wheel and hoping it runs. And believe it or not, that actually works. Gene editing is fixing the flat.Eric Topol (35:39):That's good.Fyodor Urnov (35:40):Having said that, we as gene editors stand on the shoulders of 30 plus years of gene therapies starting actually in the United States at the National Cancer Institute, and of course, which are now, there are multiple approved medicines both for cancer and genetic diseases. And I really want to honor and salute not just the pioneers of this field, but the entire community of gene therapies who continue to push things forward. But I will admit, I am biased. Gene editing is a way to fix mutations right where they occur. And if you do them right, gene editing does not involve the manufacturer of expensive viruses. Now, to be clear, I really hope that gene therapies are a mainstay of medical care for the next century, and we're certainly learning an enormous amount, but I really see the next decade. Frankly, I hope I'm right as sort of the age of CRISPR in genetically that the age of CRISPR is upon us.Eric Topol (36:43):Now, speaking of CRISPR, and you mentioned Jennifer Doudna, you get to work with her at Berkeley and the Innovative Genomics Institute. What's it like to work with Jennifer?Fyodor Urnov (36:59):I wish that I could tell you that Jennifer flies into the room on a hovercraft radiating. Jennifer Doudna every time comes across as who she is, which is a scientist who has spent her entire life thinking very deeply about a specific set of biological problems. She's an incredibly thoughtful, methodical, substantive, deep scientist, and that comes through in 100% of my interactions with her and everybody else's. Her other feature is humility. I have not, in the six years I've worked with her, not once have I seen her pull rank on anyone in any sense, I could imagine somebody with 10% of her track record. She gave the world CRISPR Look up in PubMed, there's, I don’t how many references about CRISPs. She starred an entire realm of biology and biomedicine. Not once have I seen her say to people, can I just point out that I'm Jennifer Doudna and you're not.(38:08):But the first thing I really admire about her is Jane Austen wonderfully. And satirically writes about one of her characters. He then retired to his estate where he could think with pleasure of his own importance. Jennifer Doudna is the inverse of that. She could retire and think with pleasure about her own impact. She's the inverse. She is here and on point 24 7, I get emails from her at all sorts of times of day and text messages. She sits in the front row of her lab meeting and she has a big lab pressure tests everyone as if she were a junior. Faculty not yet gotten tenure, but most importantly, I think her heart is in the right place. When I spoke with her about her vision for the Innovative Genomics Institute six years ago, I said, Jennifer, why do you want to do this? She said, I want to bring CRISPR to the world.(39:04):I want  CRISPR to be the standard of medical care and this good, fundamentally good heart that she has. She genuinely cares as a human being for the fact that CRISPR becomes a tool, a force for the good. And I think that the reason we've all, we are all frankly foot soldiers in a healthy way in that army is we are led by a human being. I jokingly, but with a modicum of seriousness. Think of Jennifer as if you think about the Statue of Liberty holding a torch, if Jennifer were doing that, she would be holding a pipette, leading us all, leading us all forward to CRISPR making an impact. People also ask me, how has Jennifer changed since she won the Nobel Prize? My answer is, she won the Nobel Prize. She hasn't, and I mean her schedule got worse. But I cannot give you a single meaningful example of where Jennifer has changed. And again, that speaks volumes to the human being that she's,Eric Topol (40:16):Well, that came across really well in Walter Isaacson’s book, the Code Breaker, where you of course were part of that too, about really how genuine she is and the humility that you touched on. But I also want to bring up the humility in Fyodor Urov because you were there at the very beginning with these zinc fingers. You were putting them into cells and showing how they achieved genome editing. There was no CRISPR, there was no Cas9. You were onto this at a very early point, and so you describe yourself just now as a foot soldier, anything but that, I see you as a veritable pioneer in this field. And there's another thing about you that I think is very special, and that is your ability to communicate this complex area and get it where everyone can understand it, which is all the more important as it gets rolled out to become a realistic alternative to these conditions that we've been talking about. So for that and so many things, I'm indebted to you. So Fyodor, what have I missed? We can't cover everything. You could write encyclopedias about this and it's changing every week. But have I missed anything that's important in the field of genome editing that you should close on?Fyodor Urnov (41:46):Well, so as far as your gracious words, now that I'm no longer blushing like a ripe tomato, I do want to honor the enormous group of people, my colleagues at Sangamo and in the academic community for building genome editing 1.0 and you among a very select few leaders in biomedicine who saw early the promise of gene editing. Again, I showcase our collaboration as an example of what true vision in biomedicine can do. I think I would imagine that your audience might say, what about CRISPR for enhancement? Well, I personally don't see anything wrong with well-informed adult human beings agreeing to being gene edited to enhance some feature of themselves once we know that it is safe and effective. But we are years, maybe a decade away from that. So if any of those listening receive an email from CRISPRmebeautiful.com, offering a gene editing enhancement service report, that email as vial spam!(43:21):CRISPR is amazing. It's affecting agriculture medicine in so many different ways and fundamental research, it's making an astonishing progress in the clinic. Medically speaking today, it is exactly where it needs to be as an experimental treatment for severe disorders, all of us have a dream where you can be crisp, you can sort of tune your genes, if you will. I don't know if I will live to see that, but for now, all of us have one prize in mind, which is make CRISPR available as a safe and effective medicine for severe existing disease. And we are working hard towards that, and I think we have a legitimate foundation for good hope.Eric Topol (44:13):Yeah, I think that's putting it very solid. It's probably now with the experience to date, not just in those hundreds of patients and in clinical trials, it continues to look extraordinary that it is going to fulfill the great, and as you said, it's not just in medicine. Many other walks of life are benefiting from this. And a lot of people don't realize that when you do a successful xenotransplant and you otherwise would die, but you give them a pig heart and you edit  50, 60 different genes in critical places so that it appears to the body as a human heart transplant, one that won’t be rejected. Theoretically, you open up areas like that that are just so exceptional. But to also highlight that we're not talking, we're talking about somatic genome editing already, genes that are sick or need to be adjusted, if you will, not the ones in embryos that change the human race. No, we're not going there. The off target affects the safety. We'll learn more and more about this in the times ahead and the short times ahead with all the more people that are getting the first lines of treatment. So Fyodor, thank you so much. Thank you for your friendship over this extended period of time. You've taught me so much over the years, and I'm so glad we have a chance to regroup here, to kind of assess the field as it stands today and how it's going to keep evolving at a high velocity.Fyodor Urnov (45:58):My goodness, Eric, it's been amazing, amazing honor. And I should also say, and this is the truth, my morning ritual consists of two things, a shot of espresso, and seeing if you've posted anything interesting on Twitter, that is how I wake up my brain to take on the day. So thank you for not just your amazing vision and extraordinary efforts as a scientist and a physician scientist, but also thank you for the remarkable work you do in making critical advances in medicine and framing them in their exact right way for a very large audience. And I'm humbled and honored by your invitation to speak with you today in this setting. Let's just say that the moment this comes out, I'm going to tell my mom. Mom, yes. What? Oh my gosh. I have spoken with Eric Topol. She will be very excited.Eric Topol (46:53):Well, you're much too kind and we'll leave it there and reconvene in the future for a update because it won't be long before there'll be some substantial ones. Peter, thank you so much.Fyodor Urnov (47:05):Truly, truly a pleasure. Thank you.Thanks for listening (or reading, or both) this Ground Truths podcastPlease share if you found it informative! All proceeds from Ground Truths go to Scripps Research. Get full access to Ground Truths at erictopol.substack.com/subscribe

Dr. Peter Hotez is a veritable force. He has been the tip of the spear among physicians and scientists for taking on anti-science and has put himself and his family at serious risk.Along with Dr. Maria Bottazzi, he developed the Corbevax Covid vaccine —without a patent— that has already been given to over 10 million people, and was nominated for the Nobel Peace Prize. Here an uninhibited, casual and extended conversation about his career, tangling with the likes of RFK Jr, Joe Rogan, Tucker Carlson, Steve Bannon, and an organized, funded, anti-science mob, along with related topics.Today is publication day for his new book, The Deadly Rise of Anti-Science.Transcript (AI generated)Eric Topol (00:00):Hello, this is Eric Topol with Ground Truths, and I'm with my friend and colleague who's an extraordinary fellow, Dr. Peter Hotez. He's the founding dean of the National School of Tropical Medicine and University professor at Baylor, also at Texas Children's founding editor of the Public Library Science and Neglected Tropical Disease Journal. and I think this is Peter, your fifth book.Peter Hotez (00:28):That's my fifth single author book. That's right, that's right.Eric Topol (00:32):Fifth book. So that's pretty amazing. Peter's welcome and it's great to have a chance to have this conversation with you.Peter Hotez (00:39):Oh, it's great to be here and great to be with you, Eric, and you know, I've learned so much from you during this pandemic, and my only regret is not getting to know you before the pandemic. My life would've been far richer. AndPeter Hotez (00:53):I think, I think I first got to really know about you. You were are my medical school, Baylor College of Medicine, awarded you an honorary doctorate, and that's when I began reading about it. Oh. I said, holy cow. Why didn't, why haven't I been with this guy before? SoEric Topol (01:08):It's, oh my gosh. So you must have been there that year. And I came to the graduation.Peter Hotez (01:12):No, I actually was speaking at another graduation. That's why I couldn't be there, . Ah,Eric Topol (01:18):Right. As you typically do. Right. Well, you know, it's kind of amazing to track your career besides, you know, your baccalaureate at Yale and PhD at Rockefeller and MD at Cornell. But you started off, I, I think deep into hookworm. Is that where you kind of got your start?Peter Hotez (01:36):Yeah, and I'm still, and I'm still there actually, the hookworm vaccine that I started working on as an MD-PhD student at Rockefeller and Cornell is now in phase 2 clinical trials. Wow. So, which is, I tell people, is about the average timeframe --about 40 years-- is about a, not an unusual timeframe. These parasites are obviously very tough targets. oh man. And then we have AOIs vaccine and clinical trials and a Chagas disease vaccine. That's always been my lifelong passion is making vaccines for these neglected parasitic infections. And the story with Covid was I had a collaboration with Dr. Sarah Lustig at the New York Blood Center, who, when we were working on a river blindness vaccine, and she said, Hey, I want you to meet these two scientists, New York Blood Center. They're working on something called coronaviruses vaccines.(02:27):They were making vaccines for severe acute respiratory syndrome and SARS and ultimately MERS. And so we, we plugged their, their, some of their discoveries into our vaccine development machine. And they had found that if you were using the receptor binding domain of the, of the spike protein of SARS and ultimately MERS it produced an equivalent protective immune response neutralizing antibodies without the immune enhancement. And that's what we wrote to the NIT to do. And they supported us with a $6 million grant back in 2012 to make SARS and MERS vaccines. And, and then when Covid 19 hit, when the sequence came online and BioXriv in like early 2020, we just pivoted our program to Covid and, and we were able to hit the ground running and it worked. Everything just clicked and worked really well. And stars aligned and we were then transferred that technology.(03:26):We did it with no patent minimizing strings attached to India, Indonesia, Bangladesh. any place that we felt had the ability to scale up and produce it, India went the furthest. They developed it into Corbevax, which has reached 75 million kids in India. And another 10 million as their, for their primary immunization. Another 10 million is adult booster. And then Indonesia developed their own version of our, of our technology called IndoVac. And, and that's also reaching millions of, of people. And now they're using it as a, also as a booster for Pfizer, because I think it may be a superior booster. So it was really exciting to s you know, after working in parasitic disease vaccines, which are tough targets and decades to get it through the clinical trials because the pressure was on to move quickly goes to show you when people prioritize it. And also the fact that I think viruses are more straightforward targets than complex parasites. And well, so that in all about a hundred million doses have been administered andEric Topol (04:33):Yeah, no, it's just a spectacular story, Corbevax and these other named of the vaccine that, that you and Maria Bottazzi put together and without a patent at incredibly low cost and not in the us, which is so remarkable because as we exchanged recently, the us the companies, and that's three Moderna, Pfizer, and Novavax are going to charge well over $110 per booster of the, the new booster updated XBB.1.5. And you've got one that could be $2 or $4 that's,Peter Hotez (05:11):And it's getting, so we're making, we're making the XBB recombinant protein booster of ours. And part of it's the technology, you can, you know, it's done through microbial fermentation in yeast, and it's been in a big bioreactor. And it's an older technology that's been around a couple of decades, and there's no limit to the amount you could scale. The yields are really high. So we can do this for two to $3 a dose, and it'd even be less, it wasn't for the cost of the adjuvant. The C P G, the nucleotide is probably the most expensive component, but the antigen is, you know, probably pennies to, to, you know, when you're doing it at that scale. And, and so that, that's really meaningful. I'd like to get our XBB booster into the us It's,Eric Topol (05:55):Yeah, it's just no respect from,Peter Hotez (05:58):We're not a pharma company, so we don't, we didn't get support from Operation Warp Speed, and so we didn't get any US subsidies for that. And it's just very hard to get on the radar screen of BARDA and those agencies and, 'cause that's, they're all set up to work with pharma companies.Eric Topol (06:16):Yeah, I know. It's, it's just not right. And who pays for this is the people, the public, because they, you know, the affordability is going to have a big influence on who gets boosters and is drivingPeter Hotez (06:27):. Yeah. So, so what I say is we, we provide, you know, the anti-vaccine guys, like the call me a Shill for pharma, not knowing what they're talking about. We've done the opposite, right? We've provided a path that shows you don't need to go to big pharma all the time. And, and so they should be embracing what we're doing. So we, we've, you know, have this new model for how you can get low cost vaccines out there. Not, not to demonize the pharma companies either. They, they do what they do and they do a lot of important innovation. But, but there are other pathways, especially for resource coordination. So we'd love to get this vaccine in, in the us I think it's looking a little work just, just as well, it's, you know, butEric Topol (07:12):You, yeah, I mean, it's not, I don't want ot demonize the vaccine companies either, but to raise the price fivefold just because it's not getting governed subsidy and the billions that have been provided by the government through taxpayer monies. Yeah.Peter Hotez (07:28):Well, the Kaiser Family Foundation reported that they did an analysis that, that pharma, I think it was Pfizer and Moderna got 25 to 30 billion Yeah. Dollars in US subsidies, either for development costs for Moderna. I think Pfizer didn't accept development costs, but they both took advanced purchase money, so $30 billion. And you know, that's not how you show gratitude to the American people byEric Topol (07:55):JackingPeter Hotez (07:56):Up the price times for, I think I said, guys, you know, have some situational awareness. I mean, do you want people to hate you? Yeah.Eric Topol (08:04):That's what it looks like. Well, speaking of before I get to kind of the anti-science, the, THE DEADLY RISE OF ANTI-SCIENCE, your new book, I do want to set it up that, you know, you spent a lot of your career besides working on these tropical diseases, challenging diseases, you know, Leischmania, and you know, Chagas, and the ones you've mentioned. You've also stood up quite a bit for the low middle income countries with books that you've written previously about forgotten people, Blue Marble Health. And so, I, I, before I, I don't want to dismiss that 'cause it's really important and it ties in with what the work you've done with the, the Covax or Covid vaccine. Now, what I really want to get into is the book that you wrote that kind of ushered in your very deep personal in anti-science and anti-vax, which I'm going in a minute ask you to differentiate. But your daughter, Rachel, you wrote a book about her and about vaccines not causing autism. So can you tell us about that?Peter Hotez (09:11):Yeah. So as you point out, my first two books were about these, what I would call forgotten diseases of Forgotten people. In fact, that's what the first book was called, forgotten People, forgotten Diseases, which my kids used to call Dad's Forgotten book on Forgotten people, Forgotten Diseases, all the, all the, now it's in his third edition. So, but it talks about, you know, the, how important these conditions are. It's just that they're widely prevalent. It's just that they're occurring among people who live in extreme poverty, including people in poverty in the United States. That's why we set up our School of Tropical Medicine on the US Gulf Coast. I didn't do it for the summer weather which is these days in this heat dome. It's like, well, living on planet Mercury right now, in here, here in Texas.(09:58):But then, so that, that's what, that's how I started learning how to advocate, you know, for people and for diseases through neglected diseases. But, you know, when we came to Texas, we saw this very aggressive anti-vaccine movement, and they were making false claims that vaccines cause autism. And, and I said, look, I'm, you know, I'm a vaccine scientist here in Texas. I have a daughter with autism, Rachel, with an, an intellectual disabilities. And so if I don't say something who does, and, and then wrote the book, vaccines did not cause Rachel's Autism, which unfortunately made me public enemy number one or two with anti-vaccine groups. but you know, it, it, it does a deep dive explaining the science, showing there's absolutely no link between vaccines and autism, but also an absence of plausibility because what we know about autism, how it begins in early fetal brain development through the action of autism genes.(10:54):And we actually did whole exome genomic sequencing on, on Rachel and my wife Ann and I, and we found Rachel's autism gene, which is like many of them in, involved in early neuronal communication and connections. It was actually a neuronal cytoskeleton gene, as are many, in this case, a neuronal spectrum. And that one hadn't been reported before, but other neuronal cytoskeleton genes had been reported by the Broad Institute at Harvard, m i t and others. And, and that was important to have that alternative narrative because the refrain from always was, okay, doc, if vaccines don't do it, what does cause autism? And, and being able to have that other side of the story, I think is very compelling.Eric Topol (11:37):What was it, the, the fabricated paper by Andrew Wakefield and the Lancet that, that got all this started? Or did it really annotate the ? There wasPeter Hotez (11:47):Something before in the eighties about the DPT, the diptheria, pertussis tetanus vaccine claiming it caused, you know, seizures and then could lead to neurodevelopmental difficulties. But it really took off with the Wakefield paper in 1998, published in The Lancet. And that claimed that the MMR vaccine, a live virus vaccine, had the ability to replicate in the colon of kids. And somehow that led to pervasive developmental disorder. That was the term used back then. And I was Rachel's diagnosis. And it never made sense to me how something, 'cause the reason it's pervasive is it's, it's global in, in the central nervous system in, in the brain. And how, how could something postnatally do something like that? I mean, there is, there are epigenetic underpinnings of autism as well, and that's fun. Eric, you ever talk to, ever try to talk to lay audience about epigenetics? That's a tough one. That's, that's a tough one. You start talking about microRNAs and DNA methylation, histone modification. The, the lights go out pretty quickly, butEric Topol (12:46):Chromatin and histone modification. Right? Bye-bye. Yeah, you got that one.Peter Hotez (12:51):That, so that's,Eric Topol (12:52):But that, that was your really, you knowPeter Hotez (12:55):But that's when, you know, I started going up against Robert F. Kennedy Jr. And, and, and all that was, that was pre-pandemic.Eric Topol (13:03):That was in 2018, right?Peter Hotez (13:05):2017 Trump came out and said, you know, it was about to be inaugurated and, and RFK Jr said he was going be appointed to run a vaccine commission by the Trump administration. And, and I actually was sitting, you know, in my office and my assistant said Dr. Francis Collins and Dr. Anthony Fauci are on the phone. Do you have time to talk with us ? And I said, yeah, I think so. And they arranged, they had arranged for me to, because I have a daughter with autism could articulate why vaccines don't cause out arranged for me to speak with RFK Jr threw it through a mediator and, and, and it didn't go well. He was just really dug in and, and soEric Topol (13:49):He, he was just as bad then as now.Peter Hotez (13:52):Yeah. I mean, it was just, you know, kept on, you know, as I say, moving the goalposts, you couldn't pin him down. Was he talking about MMR? Was he talking about the am Marisol, was he talking about spacing vaccines too close together? He just, that always kept on moving around and, and then it was not even autism at times. You were talking about it was something called chronic illness, you know, you know, what do you do with that? Mm-hmm. . So I, and that's one when I was challenged by, you know, Joe Rogan and Elon to debate RFK Jr, one of the reasons I didn't want to do it, because I, I knew, you know, doing it in public would be no different from doing this in, in, in private, that it would not be a productive conversation.Eric Topol (14:39):Yeah, no, that I can, I do want to get into that, because that was the latest chapter of kind of vicious anti-science, which was taking on covid and vaccines and the whole ball of wax whereby you were challenged by Joe Rogan on his very big podcast, which apparently is, you know, bigger than CNN  various cable news networks,Peter Hotez (15:07):Which I had done, I had been on his show a couple of times. Yeah. And that was, and that was okay. I mean, I actually liked the experience quite a bit. AndEric Topol (15:15):And he challenged you to go on with RFK Jr. And then Elon Musk, you know, joined and, you know, basically Peter Hotez (15:21):Actually, he started before then, about the week before, or a few days before, Steve Bannon publicly declared me a criminal. And you know, which I said, wow, that's, that's something. And then Roger Stone weighed in. So it was this whole sort of frontal attack from, well, people with extremist viewpoints. And there'sEric Topol (15:41):Been a long history, and a Tucker Carlson in the book, you quote, he referring to Hotezis a misinformation machine constantly spewing insanity. Speaking of projecting things, my goodness. Yeah.Peter Hotez (15:54):Yeah. Well, he did that. You know, he, that was the, that was in 2022. It was, he went on his broadcast the evening after the evening of the, in the, during that day I, with Maria, I was, we were nominated for the Nobel Peace Prize. And I guess, and I don't know if the two are related or not, I think it may have driven him off the edge, and then he just went on this rant against me. And, you know, claimed I have no experience anything about Covid. I mean, we had made two covid vaccines, right. And transferred the technology nominated for the Nobel Peace Prize and just, you know, omitted all of that. But this is how these guys work. It's, it's all about asserting control. And, and it seems to come from an extremist element of the, of the far right.(16:39): and, and, and it's not that I'm a very political person at all. I mean, you know, I've been here in Texas now for 12 years, and I've gotten, you know, I've gotten to know people like Jim Bakker and his wife Susan Baker and, and you know, a lot of prominent Republicans here in Texas, that that wasn't an issue. This is something sort of weird and, and twisted. And, and the point that I make in the book is, and it's not just a theoretical concern or a construct, it's the fact that so many Americans lost their lives during the delta and BA.1 omicron waves in 2021 and 2022, after vaccines were widely and freely available because they refused a vaccine. so vaccines were rolled out in 2021. we started strong and then vaccination rates stalled. And then we didn't get very far by this after the spring because there was this launch of an, of, of a wave of what I call anti-vaccine or anti-science aggression, convinced that deliberately sought to convince Americans not to take a covid vaccine.Eric Topol (17:56):Chapter, yeah. Your chapter in the book Red Covid. Yeah, gets into it quantifies it, hundreds of thousands of lives lost. And I know you've seen some of the papers whereby studies in red states or states like Ohio and Florida showing the, the, the connection between this.Peter Hotez (18:15):Yeah, I, I relied heavily on this guy Charles Gaba, who has a, a website called ACA signups. And he did some really in, you know, strong analysis showing that the, that the people who were refusing covid vaccines and losing their lives were overwhelmingly in red states and could even show the redder the county as measured by voters, the lower the immunization rate and higher the death rates. And the term Red Covid came from David Leonhart of the New York Times wrote an article about Charles Gaba's work, and he called it Red Covid and did a lot of updates. And the data is so strong. I mean, so much so that one person at the Kaiser Family Foundation wrote, if you wanted to ask me whether or not a person was vaccinated, and I can only know one thing about them, you know, she said, the one thing I'd want to know is what political party they're affiliated with.(19:09):It was, it's, it's that strong. And it's, and it's not that I care about your politics, even your extreme views, but somehow we have to uncouple this one from it, right. Because somehow not getting vaccinated been added to the canon of stuff that you're supposed to believe in. If you are, if you're down that rabbit hole watching Fox News every night, or, or listening to Rogan Podcasts and that sort of stuff. And somehow we have to uncouple those two, and it's the hardest thing I've ever had to do. First of all, it's unpleasant to talk about, because all of, you know, your training, Eric mine as well is, you know, said you don't talk about politics and you're, you know, we're supposed to be above all that. But what do you do when the death and dying is so strong on, on one side?(19:58):And, and I, I was in east Texas not too long ago, giving grand rounds at a new medical school in East Texas and Tyler, Texas, and very conservative part of the state. And, you know, basically everyone you talked to has lost a loved one mm-hmm. because they refused a Covid vaccine and died. I mean, that's, that's where you really start to see that. And then, and these people are wonderful people. I gave you know Bob Harrington at oh yes, at at Stanford Medicine, now he's going be the Dean of Cornell. He, he invited me with Michelle Berry to, to give grand rounds, medical grand rounds at Stanford. And I said, look, if, if my car had broken down and the flat had a flat tire, and you, and I can't fix, I'm, I'm a disaster at fixing anything.(20:49):So if you said, okay, where you had the choice, where, where do you want your car broken down in Palo Alto, California, or Stanford is, or very wealthy enclave or East Texas, I'd say I'd pick East Texas in a second. 'cause in East Texas, they'd be fighting over who you know, is going to rush to help you change your tire. Right? And these are, you know, just incredible people. And they were victims. They were victims of this far right. Attacks from, from Fox News. And one of the things I do in the book is, you know, the documentation is really strong media matters. The Watchdog group has looked at the evening broadcast of Tucker Carlson, Laura Ingram, and, and Hannity, and, you know, can I, you know, actually identify the anti-vaccine content with each broadcast during the summer and fall. And then our a social science research group out of ETH Zurich, the Federal University of Technology of Zurich, where Einstein studied, actually, you know, one of the great universities did another analysis and showed that watching Fox News is one of the great predictors of refusing a vaccine.(21:52):And, and so that, those were the amplifiers, but those generating a lot of the messages were elected leaders coming out of the House Freedom Caucus, or Senator, you know, Johnson's conservative senate that, I don't even like to use the word conservative, because it's not really that they're conservative, they're extremists. And yeah, a Senator Johnson of Wisconsin, or Rand Paul, you know, of, of Kentucky, you know, all the physician know what Yeah. And know physician and the CPAC conference of conservatives in Dallas, in 2021, they said, first you're gonna, they're going to vaccinate you, and then they're going to take away your guns and your Bibles. And as ridiculous as that sounds to us, people in my state of Texas and elsewhere in the South accepted it and didn't take a covid vaccine and pay for it with their lives. And, and how do we, you know, begin walking that back?(22:45):And, and the point of writing the book said, well, the first step is to at least describe it so people can know what we're talking about. Because I think right now, when you look at the way people talk about anti-vaccine or anti-science stuff, they, they call it misinformation or the infodemic, like it's just some random junk that appears out of nowhere on the internet. And it's not any of those things. It's, it's organized, it's well financed. It's politically motivated, and it's killing Americans on, on a massive scale. So I said, look, you know, I, I went, I'm did my MD and PhD in New York at Rockefeller and Cornell. I devoted my life to becoming a vaccine scientist. You know, the motto of Rockefeller universities to be the Rockefeller Institute of Medical Research translates to science for the benefit of humanity. And, and I believe making vaccines is one of the high expressions. And I think most physician scientists believe, I think you believe that too. And that's why you're, you're in this as well, you know, not vaccines, but you know, other lifesaving interventions. And, and so I said, well, now making vaccines is not enough. 'cause now we have to counter all of this anti-vaccine stuff, and there's, there's nobody better, you know, in terms of my training and my background going up against anti-vaccine movements because of Rachel to do this. So I, I've done it and yeah.Eric Topol (24:11):Well, you've done it. All right. you,Peter Hotez (24:14):That's my wife. Ann says you've done it. Alright, .Eric Topol (24:17):Well, as I wrote in your, with your book of blurb about you are a new species, the physician scientist warrior, and you are Peter, because you're the only one of all the physicians. We're talking about a million docs almost in this country who has stood up and you've put your life at risk, your family at risk, you've had death threats, you've had the people you know, come right to your house. and so what you've described this kind of coalescence of political will of extremists, media, of course, amplification because it benefits them. They, they're selling more you know, they get more viewers, more the spots for commercials and more they can charge. And then you're even, as you described in the book, so well, is you even have outside interested parties like Russia as part of this organization, of this coalescence of forces that are taking on the truth, that are promoting anti-science, that are winding up, people are dying, or, yeah. Or having a, you know, serious morbidity,Peter Hotez (25:26):Right? Yeah. In the case of, in the case of Russia, , it's a slightly different motivation. What they're doing is they're filling the internet and social media with both anti-vaccine messages and pro-vaccine messages. Because they have a different agenda. Their agenda is destabilized democracies. So what they're doing is they're cherry picking certain issues that they can use as a wedge to sow discord. And so when they saw the stuff about vaccines, yeah, they'll flood it with both pro and anti-vaccine message. And you see the stuff on Twitter, so much of it is computer generated, and it's just repeats the same stuff over and over again. And, and a lot of that are, you know, some of that not only, only Russia, I think China's doing it, North Korea, Iran's doing it, but particularly Russia. And that was documented by a colleague of mine, David Broniatowski who's a computer scientist at George Washington University, has really done a deep dive in that. So so'sEric Topol (26:22):I think a lot of people are not aware that's what your book, book brings to light of how organized, how financed, you know, how this thing is a machine from coming from many different domains, you know, and for different interests as you, as you just summarized, it's, it's actually scary. And besides you standing up and facing, you know, the really ultimate bravery with the, all of the, these factions attacking you, literally ad hominem, you know, personally attacking you, then you have you know, this continues to get legs throughout the pandemic, and there's no counter as you've, as you've touched on what is going to be done. You can't stand up alone on this.Peter Hotez (27:09):Well, there's, there's a couple of things. First of all, it's not only attacking the science, it's attacking the scientists. Right, right,Eric Topol (27:15):Right.Peter Hotez (27:16):Exactly. It's, it's portraying and you get get it too, as well. I mean, it's basically portraying scientists as enemies of the state. which I think is so dangerous. I mean, as I like to say, you know, this is a nation that's built on science and technology, right? The, you know, the strengths of our research universities and institutions like Scripps, like Baylor, like Rockefeller, like MIT and Stanford, and University of Michigan and University of Chicago. This is what, you know, helped us defeat fascism in World War II as evidenced by the Oppenheimer movie, right. Or, and or allowed us to achieve so many things, why people so admire our nation. When I served as US Science Envoy and the Obama administration, the State Department, and the White House. I mean, that's where people loved our country, is they all wanna study at our research universities, or they want their kids to study at our research universities.(28:10):And, and by attacking not only science, but the scientists, I think it's weakening our stature globally. And, and, and, and I think that's, that, that's another aspect. I think the other problem is we, we don't get the backing that I think we should from the scientific societies in the Times, even the National Academies. I think they, they could be out there more. exactly why, you know, I think part of it is they see, they see how I get beat up and they say, well, what's that? Right? Yeah. And I, and I understand that, but I think also, you know, they, they depend on, oftentimes on government funding. And I think they're worried that, you know, if they're, again, it's this idea that you have to be politically neutral, even if it favors the torment or the aggressor to paraphrase Desmond Tutu, that's part of it as well.(29:09):I mean, it, I mean, I do find it meaningful. It's scary at times, and I, but I do find it meaningful to ha to have this role. But getting, getting more help and backing, I mean, we're our, our university, I mean, Baylor College of Medicine, Texas Children's Hospital has been pretty good. You know, Stan, you know, having my back, it's not that way at every, and I know Scripps has been really strong with what Kristian Anderson's had to deal with around you know, all the phony bologna around covid origins. But, but not all academic health centers are that way. And, and I think we need our university presidents to be more vocal on this issue. And, and too often they're not as well as our academies and our, our scientific societies, because this is, I believe, going to do irreparable harm to, to science. Well, yeah.Eric Topol (30:04):You know, in my experience too, we, we've actually seen, you know, academic physicians who have basically, you know, supported conspiracy theories who have detracted from evidence and science, you knowin a major way. Some of the leading universities here as you, as you mentioned. And when I've contacted and others, their leadership, they say, well, freedom of speech, freedom of speech. 'cause they're afraid to confront them because, you know, all the different things. We've, we, you've mentioned social media, but no, the universities don't want to get attacked on social media. They're afraid of that. They're afraid of, of calling out, you know, one of the people, faculty members who are deliberately, you know garnering a lot of, yeah. And,Peter Hotez (30:56):And the point is, is it's not just, you know, freedom of speech in the sense of espousing you know, crazy views. It's the fact that they're going on the attack against mm-hmm. . I mean, I don't attack these guys, but they attacked me with, with impunity and Yes. Say terrible thing, untrue things about me. I mean, where's there's, isn't there something called professionalism or, or ethics, yeah. Right. That don't, don't, don't, don't we, aren't we supposed to be in instilling that in our, in our faculty and, and that that doesn't seem to happen.Eric Topol (31:28):So that'sPeter Hotez (31:28):Troubling asEric Topol (31:29):Well. They're, they're making credible scientists who are doing the best they can into pinatas Right. And attacking them. And with, and it can't, it can't be reciprocated because that's, that's beneath professionalism. I mean, just as you say. So, you know, you just keep, they just keep going at it. So what you have is now we've added all these different entities and all add more. One more is ai, which is going to further blur the truth.Peter Hotez (31:59):Yeah, Renee DiResta at the Stanford Internet Observatory, I don’t if you know Renee, she does fabulous work. And she's written about, you know, what happens when, you know, all of the anti-science, anti-vaccine stuff is now imbued with ai, and, you know, it's going become even more sophisticated and more difficultEric Topol (32:17):To No, there's, there's gonna be a video of you saying that, you know, these vaccines are killing people but don't get a booster and it'll be just like you with your voice. Yeah.Peter Hotez (32:28):Well, they already, they already have. Now these, there's these few things on YouTube that, that claim, I'm secretly Jack Black, the actor . And that the CIA has arranged it so that Jack Black plays this fictional character named Dr. Peter Hotez. And they do all these things like, you know, focus in on my eyes and do like eye identification. It's just, it's just nuts. I mean, what, what's out there?Eric Topol (32:54):Well, has there been a time in these months where you were very scared you, you're for yourself or your family because of all the incredible density and, and what appears to be very serious threats and duringPeter Hotez (33:08):, during, during the day, during the day, I'm okay. I mean, in, you know, when the, when the, when the Steve Bannon in stuff and Joe Rogan stuff, then I had the stalking at the house, and, you know, I had to have a Houston Police Department officer parked in front of my house or a Harris County Sheriff that, that was troublesome. But it, it's more of during the day, I am fine. I'm working, I'm talking, you know, to people like you and in lab meetings, doing what scientists do, writing grants and throwing pencils at the wall when you get a paper with a major review or, or a major revision or rejection. But, but it's, I think at night, you know, wake up in the middle of the night and the, it's, the stuff does start to mess with your head at times. And it'sEric Topol (33:54):Well, and you travel a lot and you, you've, I think expressed that, hey, you could be given a talk in an innocent place and somebody could come, you know, attack youPeter Hotez (34:04):There. Yeah. So I have to, I have, I have security now at, in major venues when I speak. and, you know, I had an, there was an incident at the World Vaccine Congress in Washington. There were protesters out in front of the, out in front of the convention center waiting for me that that wasn't fun. And so, even, you know, we've got, we'll see what happens with the, when the, you know, I'm doing a number of events around the book in Washington DC and New York and elsewhere. We'll, we'll see how that goes. soEric Topol (34:38):Well take it. You, you're, I know you well enough to know that you're an optimistic person. I mean, you've been smiling and we've been laughing during this and discussing some very heavy, serious stuff. What gives you still optimism that this can someday get on track?Peter Hotez (34:57):Well, I think it could get worse before it gets better, first of all. And, and two fronts. One, you know, I had the opportunity to meet with Dr. Tedros, the World Health Organization Director, general of World Health Organization towards the end of last year. And to say this could be the warmup act in the sense that now it's globalizing. I'm anticipating spillover all childhood immunization rates. And, you know, you're starting to see the same US style of anti-vaccine rhetoric now, you know, even in low and middle income countries on the African continent in South Asia. So I worry about, you know, measles and polio, both in the US and, and globally. I think that's, that's, I'm worried about that. The other is, you know, a lot of this is heating up, I think because of the 2024 presidential election. I think one was that with, with our, our mutual friend and colleague Anthony Fauci, now that he's out of government he's not as visible as he was.(35:58):I think they're, the, the extremists are looking around for another, they need a monster right. To, to galvanize the base. And I think I've become that monster. You know, that's, that's one thing I'm worried about. But also you with, I talk to probably someone you've seen on Twitter. and I've gotten to know her somewhat, I'm very impressed with her. Molly Chong Fast, who's a commentator on c n at M S N B C, and she, you know, put out there, and she told me privately and put it out in public that, you know, one of the reasons why things are so vicious around RFK Jr, as they see him as a third party candidate that could take Biden votes away and help create a path for Trump being elected. So by, you know, by having me debate him, it, it kind of elevated in, in its own way, elevated his stature and made him seem like a more serious person. Right, right. And my refusal, you know, popped their bubble. And that, that's one of the reasons why, why they're so angry. So this is very much tied, I think, to the 2024 presidential look. And that's what you're having seen with the House subcommittee hearings too, portraying scientists as enemies of the state. It's all for, I mean, I don't know if you've seen this, the, that House Subcommittee Twitter site, it actually says something like, we're selling popcorn, you know, we'reEric Topol (37:18):Yeah, I know. I mean,Peter Hotez (37:20):They're, they're not, they're not even pretending it's anything, theEric Topol (37:23):PoliticalPeter Hotez (37:23):Theater for Fox News soundbites. So I think we're gonna see they're the word.Eric Topol (37:27):Alright. Yeah.Peter Hotez (37:28):Yeah. And, and, but, you know, but the attacks on biomedical science, I think are gonna be, you know, have a long-term effect. If for no other reason, I think people are gonna think twice about wanting to do a PhD in biomedical scientist or become an MD PhD scientist when they see that, you know, we'reEric Topol (37:47):. Well, that's what you, you also covered that really well in the Yeah. In the book. But when you think about where we are now with climate crisis, or we're facing future pandemics, not just the one we're still working through here where is the hope that we can counter this? I mean, we need armies of people like you. We need, as you say, the scientific establishment and community all stand up. That, that gets me to one of the things that makes you differentiates you from most physicians and scientists. You write books, you are active on social media. You, you appear on the media. Most scientists grew up to have their head do the work, do good science, get their stuff published, and get grants and, you know, try to advance the field and physicians doing that, are taking care of patients, same kind of thing. What prompted you in your career to say, Hey, you know, that's not enough. I got another dimension. And why, how can we get millions of clinicians and scientists to rally to do what you'rePeter Hotez (39:01):Doing? Well, in my, in my case, I, it's not that I was deliberately seeking to be a public figure or what some call a public intellectual. It was more the case, the issues that I was most interested in, nobody was talking about. Mm. And nobody was going to talk about it. So if I didn't talk about it, it wasn't gonna be talked about. So neglected tropical diseases, you know? Yeah. For guard people was, and, and I had two colleagues in the uk, Alan Fannick and David Mullen, who felt the same way. And so we began be, we became the three Musketeers of the neglected tropical disease space. And I found that extremely meaningful and interesting. And it was the same with vaccines. So although I, I'm often in the, you know, doing a lot of public engagement, if you notice, I don't try to be like some people who do it very well, like as Sanjay Gupta or, or some others that will, or Megan Rainey that will talk about, you know, just about any health issue.(39:56):I, I don't try to do that. I sort of stay, it's a wide lane, but I try to stay in my lane around infectious, neglected diseases and, and, and vaccines. And I think that's very important. Now, in terms of, you know, the statement, most scientists or physician scientists wanna keep their head done, write their grants and paper. I think that's perfectly fine. I don't think you people should be forced to do it, but I think there's enough of us out there that wanna do it, but don't know how to get started and don't feel safe doing it. I, and so I think we need to change that culture. Mm-hmm. I think we need to offer science communication to our graduate students in their PhD programs or in MD PhD programs for those who wanna do it, or in residency training or fellowship training. And so that, because there, there are things you can learn.(40:46):I mean, we had to do it by trial and error, and in my case, more error than trial. But, but, but there is a, there is, there are things you can learn from people who do this professionally. So I think that's important. I think the other is we need to change the culture of the institutions. You know, I, I get evaluated just like you do like everybody, like any, you know, senior scientist or professor at university, and, you know, what do they ask me about? They ask me about my grants and, and my papers preferably in high impact journals, and they ask me, and I don't see patients anymore, so they don't ask me about my clinical revenue, but they ask me about my grants and papers and my grants and papers, and my grants and papers. There's not even any place on my form, my annual evaluation from, to put in the single author books. I've written much less, you know? Yeah. The, the opinion pieces I've written, or certainly not social media or even, or even the cable news channel. So, so it basically, the academic health center is sending the message. And I don't think that's unique. I think that's probably the rule in most places. I think the, the culture of academic health centers is they're basically, they're sending a message just saying, well, we don't consider that stuff important, and somehow we have to make it important. I think for those who wanna do itEric Topol (42:08):AbsolutelyPeter Hotez (42:09):To send that message,Eric Topol (42:10):You're, you're, you're pointing out a critical step that has to be undertaken in the future. it'll take time to get that to gel, hopefully, but if it's promoted actively, I certainly promote that. I know you do. Yeah. I think,Peter Hotez (42:23):I think most, most offices of communications at academic health centers, as I said, Baylor and Texas Children's is pretty good, better than most, but most, you know, don't even like their docs and scientists speaking out. Yeah. Right. They wanna control the message. It's all about, you know, they're very risk averse. They're protecting the reputation of the institution. They only see the risk side. They don't, you know, you know, you wanna speak about social justice or, or combating anti-science. Well, you know, we guess we can't stop you, but they sort of cringe at, at the idea. And then, you know, they say, well, you know, ultimately you're a professor or a scientist here, you have academic freedom.com, but don't screw this up. Right. And don institution at risk. Right.Eric Topol (43:07):Ab you're describing exactly how university communications worked.Peter Hotez (43:12):Yeah. ButEric Topol (43:13):ThePeter Hotez (43:13):Point is, and so you do it with the sort of Damocles over your head, and, and you know, as you know, and as anyone knows, if you do enough, you will screw it up eventually, right? Everybody does. And, and you know, you're gonna make mistakes. That's how you learn. You make mistakes and you, you auto correct. But, but you have to have that freedom to be able to make mistakes and Yeah. And right now that's not there either.Eric Topol (43:35):What, what you're driving at though altogether is that we're defenseless. That is, if you have an organized finance coordinated attack on science, and also of course on vaccines, and you have no defense, you have, I mean, it's hard for the government to stand up because they're part of what's the conspiracy theory is, is, is against, and you, and, and the scientific community, the clinician community is, you know, kind of handcuffed as you are getting at. And also, you know, that's not the culture that's unwilling, but something's gotta give. And this is one thing I think you're really reinforcing that, that should a pathway to countering. I mean, we can't clone you. You know, we can't, we need lots of warriors. We need, you know, thousands and hundreds of thousands of points of light who support data and evidence, you know, as best that they can. And we don't have that today.Peter Hotez (44:36):Yeah. And we, we need to cultivate that. So I'm in discussions not only with people like yourself, but other colleagues about should we try to create, whether it's a nonprofit of 5 0 1 C three or C four the climate scientists are ahead of the game on this. Yeah. Yeah. I, I talk to Michael Mann every now and then, and, you know, they've got a climate science defense fund. They, they seem to be, 'cause it, they've, they've experienced this for longer than we have. You know, the, this all started a decade before with tax against climate scientists, you know, should, in the book I talk about, should we create something like a Southern Poverty Law Center equivalent to, to protect science and scientists? And, and I think we need that because the existing institutions don't seem willing to, to create something like that. It's somehow seen as too edgy or too out there and Right.(45:30):And it shouldn't be. But, but again, this is a I think a, a great opportunity for college presidents to, to step up and, and they're not doing that. They're, they're also pretty risk averse. So I think, you know, getting, getting the heads of the academic health centers, getting the college president, university presidents to say, Hey, this is important because otherwise science is at risk. And, and you're already starting to see some crazy stuff come out of the N I h now about doing international research. They're trying to put in rules to say they want, you know, if you have international collaborators, you're supposed to collect their notebooks and translate the how are you gonna do that? That's, that's completely, IM it's important. I mean, it's, and who's gonna review it and who's gonna sign off in general legal counsel at the university on, that's basically gonna halt international research. And we have to recognize that we need this because the threats are coming. Right? I mean,Eric Topol (46:33):CliPeter Hotez (46:34):Climate change is real, and pandemic threats are real. We're gonna see another major coronavirus pandemic possibly before 2030 or a flu or an arbovirus. And, and we're, we're, we need, this is a time we need to be reinforcing our, our virology research and our infectious disease research, not a time to, you know, start dismantling it, which is what totally the house hearings are, are meant to do, and what some of these new n i h rulings are meant to do. So it's gonna take a lot of strong players and, and, and government and at universities to stand up to this.Eric Topol (47:14):Well, if we ever need to be vaccinated or immunized, it's against this. And I hope that something will give to start to provide an antidote to what is a relentless progression of united science that you so elegantly eloquently in, in your book, Peter. So thanks for writing that. thanks for joining today. I know we'll have, as we do every week conversations yeah. You,Peter Hotez (47:41):You've been a, you've been an amazing friend and colleague, Eric, and I've learned so much from you. And, andEric Topol (47:46):No, no. I, I feel I can't tell you thank you. I, I, I think it's completely reciprocal from what you bring to this table of trying to make this a better place for advancing science search for, for the truth of what's really going on out there, rather than having to deal with wacky, you know, extremists that are advancing things for various purposes that are, that are nefarious in many cases. So, appreciate it. we'll be talking some more and this has been a really for me, an enriching conversation.Peter Hotez (48:21):Same, same Eric. And thank you so much for giving this attention and the dialect to be continued.Thanks for listening, reading and subscribing to Ground Truths!Please share if you found this podcast worthwhileFull video link Get full access to Ground Truths at erictopol.substack.com/subscribe

Few, if any, physician researchers have done more to understand the long-term impact of Covid than Dr. Ziyad Al-Aly, a professor, nephrologist, and epidemiologist along with his team at Washington University, St. Louis. Here is the transcript (with links to the audio) of our conversation that was recorded one 7 September 2023.Eric Topol (00:00):Welcome to Ground Truths, and this podcast is a special one for me. I get to meet professor Dr. Ziyad Ali for the first time, even though we've been communicating for years. So welcome, Ziyad.Ziyad Al-Aly (00:15):Well, thank you. Thank you. Thank you for having me. It's really a delight and pleasure and an honor to be with you here today. So thank you. Thank you for the invitation, and most importantly, thank you for all the stuff that you do and you've been doing over the past several years, communicating science to the whole world, especially during the pandemic and enormously grateful for all your effort.Background in Lebanon, the move to Wash U., and EpidemiologyEric Topol (00:33):Well, you're too kind and we're going to get into your work, which is more than formidable. But before I do that, because you have been a leading light in the pandemic and understanding, especially through the large veterans affairs population, the largest healthcare system in the United States, the toll of covid. But before we touch on that a bit on your background first, you're a young guy. You haven't even hit 50 yet, my goodness. Right. And you grew up in Lebanon, as I understand it, and you were already coding when you were age 14, I think, right? Pretty wild. And then perhaps the death of your father at a young age of multiple myeloma had a significant impact on your choice to go into medicine. Is that right?Ziyad Al-Aly (01:28):Yeah, that's how it is. So I grew up in Lebanon, and when I was growing up, the computer revolution at that time was happening and all of a sudden in my surroundings, there's these people who have these Commodore 64. So I decided that I wanted one. I asked my parents to get me one. They got me one. I learned coding at that age, and my passion was I thought I wanted to do then why not to do computer science. And then my dad fell ill with multiple myeloma and it was an aggressive form and he required initially a lot of chemotherapy and then subsequently hospitalizations. I do remember vividly visiting him in the hospital and then connected with the profession of medicine. I was not on that track. I didn't really, that's not all my youth. I wanted to be a coder. I wanted to be a computer scientist. I wanted to do basically work with computers all my life. That's what my passion was. And then redirected all that energy to medicine.Eric Topol (02:32):Well, you sure did it well. And you graduated from one of the top medical schools, universities at American University of Beirut, and came to St. Louis where you basically have for now 24 years or so, went on to train in medicine and nephrology and became a leading light before the pandemic. You didn't know it yet, I guess, but you were training to be a pandemic researcher because you had already made the link back in 2016, as far as I know, between these protein pump inhibitors and kidney disease later, cardiovascular disease and upper GI cancers. Can you tell us, was that your first big finding in your work in epidemiology?Ziyad Al-Aly (03:22):Yeah, we started doing epi. I started doing epidemiology or clinical epi right after fellowship, trained with mentors and subsequently developed my own groups and my own funding. And initially our initial work was in pharmaco-epidemiology. We were very, very interested in figuring out how do we leverage this big data to try to understand the long-term side effects of medication, which was really not available in clinical trials. Most clinical trials for these things track them for maybe 30 days or at most for few months. And really long-term risk profile of these medications have not been characterized previously. So we did that using big data and then subsequently discovered the world of environmental epidemiology. We also did quite a bit of work and environmental linking air pollution to non-communicable disease. And in retrospect, reflecting on that now, I sort of feel there was training ground that was training wheel out, how to really optimize our thinking, asking the right question, the right question that matters to people addressing it rigorously using data and also communicating it the wider public. And that was my training, so to speak, before the pandemic. Yeah,Eric Topol (04:37):Yeah. Well, you really made some major, I just want to point out that even though I didn't know of your work before the pandemic, it was already momentous the link between air pollution and diabetes, the link of PPIs and these various untoward organ events, serious events. So now we go into the pandemic and what you had access to with the VA massive resource, you seize the opportunity with your colleagues. Had some of this prior work already been through that data resource?Ziyad Al-Aly (05:18):Yes, yes. Our work on PPI on adverse events of medications, including proton pump inhibitors, was all using VA data. And then our work using environmental epidemiology, linking air pollution to chronic disease was also using VA data. But we linked it with NASA data with sort of satellite data from NASA that capture PM 2.5. But NASA has these wonderful satellites that if a chemical is on earth and has a chemical signature that can actually see it from space and measure its concentration. So that data is actually all available free of charge. So what we did is I went to these massive databases at NASA and link them to our VA data, and then we're able to analyze the relationship between exposure to high levels of air pollution in the United States and then subsequent disease in veterans in our database.Eric Topol (06:11):That was ingenious to bring in the NASA satellite data. Big thinker. That's what you are. So now you are confronted with the covid exposure among what millions of veterans. Of course, you have controls and you have cases and you're now seeing data that says every system is being hit here and you write, you and your colleagues wrote papers on virtually every system, no less the entire long covid. What were the surprises that you encountered when you were looking at these data?Initial Shock on Covid’s Non-Pulmonary Sequelae IdentifiedZiyad Al-Aly (06:47):I remember the initial shock and our first paper when we did our first paper and there was a systematic approach looking at all organ systems. We weren't expecting that because at that time we were thinking SARS-CoV-2 is a respiratory virus. We know respiratory virus may have some post-acute sequela and maybe cardiovascular systems, but we weren't really expecting to see hits in nearly every organ system. And remember when we first got the results from what then became our nature paper, our first paper in nature around this, I doubted this. I couldn't really believe that this is really true. I looked at the association with diabetes and I told Yen, my colleague here who's really absolutely, absolutely wonderful, told him, there must be a mistake here. You made an error. There's an error in a model for sure. This is not believable. That can't be like SARS-CoV-2 and diabetes.(07:39):This is impossible. There wasn't really an arrow in my brain that sort of linking SARS-CoV-2 diabetes. I doubted it. And we went back to the model, went back to the data, rebuilt the cohort, redid the whole experiment again with controls. The same thing happened again. I still was not believing it, and it was like, end, there is something wrong here. It's weird. It's strange. This is not how these things work. Again, from medical school, from all my education, we're not trained to think that viruses, especially respiratory viruses, have these myriad effects and all these organ systems. So I doubted it for the longest time, but the results came back exactly consistent every single time the controls work, our positive control work, our negative controls work. Eventually the data is the data, then we then submitted it for a review.The Largest Healthcare System in the United StatesEric Topol (08:40):Yeah. Well, I want to emphasize this because many have tried to dismiss their data because it's average age of 60 plus and it's men and it's European ancestry and for the most part, but everything you found, I mean everything you found has been backed up by many other replications. So for example, the diabetes, particularly the Type 2 diabetes, there's now 12 independent replications and a very similar magnitude of the effect, some even more than 40% increase. So we didn't need to have more in the diabetes epidemic than we already have in the world. But it looks like Covid has contributed to that. And what do you say to the critics that say, oh, well these are old white men are studying and does it really apply long and all this multi-system organ hits to other populations given that, for example, the prototypic long covid person affected might be a woman between age 30 and 39. What's your sense about that?Ziyad Al-Aly (09:54):The way I think about it is that our data are massive. And while the average age is 60, the data, because these are literally millions of people, some cohorts are 6 million. Some of the studies that we've done, 6 million people, so the average age could be 60, but there are literally hundreds of thousands in their twenties and thirties and forties, and they're all represented in the data. And the data is obviously also controlled for age and race and sex. And I tell people this thing that they say, oh, well, your data is only 10% women, and then this is why. But 10% out of 6 million people is 600,000 women. I told a friend the other day that 600,000 women could fill six Taylor Swift stadiums. So it isn't really small. And even if we were to only analyze people in their twenties and thirties, or we could do that, we could do that.(10:44):We could easily do 300 or 400,000 people study of people from age 20 to 40. In our experience, we get more or less the same results because again, the results are adjusted for age. And then the second component of my thinking about this, and as you pointed out, the gold standard and science is reproducibility. Does this really finding reproduce in other settings? Other people are also seeing it, are able to validate it and reproduce the finding. Or this really some peculiar thing about the VA is happening only in the VA world or the VA universe. That doesn't really happen outside. And then so far, not only the findings in the pandemic, all the findings prior to the p p use and chronic kidney disease, PPI use and other side effect, all the pollution work has been reproduced to the T by Michelle Bell by Francisca Doci at Harvard to the T.(11:35):All these pollution studies have been reproduced from using Medicare data using data that's outside the VA, other data sets. And also some European friends and European collaborators reproduce the same thing. So again, the gold standard in science reproducibility, but healthy skepticism is skepticism is also healthy because we always want to challenge the finding. Is this really true? Can we bank on it? And really the most important thing inside reproducibility really is to be able to take this finding or to take the question somewhere else and then be able to reproduce the evidence that is seen in any dataset.The New 2-Year Follow-Up StudyEric Topol (12:13):Right. Well, so you have really laid out the foundation for our understanding of Long Covid. I agree with your point that there's plenty of people who are more in that prototypic age and gender. But by doing so, we have these kind of two paths. One is the symptoms of Long Covid where as you know, there's reported even a couple of hundred and some of course in clusters. And then there's these organ hits across neurologic, cardiovascular, kidney, and on and on. And you recently of course provided the two year data on that, which of course is important because as you know from your data, these are mostly, if not almost exclusively unvaccinated early in the pandemic. Could you comment about what your main findings were in two years and what you think would be the difference if this was a widely vaccinated population?Ziyad Al-Aly (13:20):Sure. In the two year studies, what we've really seen is that we, first of all, to introduce the readers or the listeners, there were two groups. We split them into two cohorts, non hospitalized and hospitalized people with covid 19 compared to controls. Now in the non hospitalized group, in both groups we assessed about 80 sequela of SARS COV to two. We've seen about 30% the risk for 30% of the SQL remain elevated at two years in the non hospitalized group, those are the people who really had mild disease that did not necessarily hospitalization yet even at two years, they remained at higher risk of about 30% of the sequela that we evaluated in that study. The risk profile for the people who were hospitalized was much more complicated or much more or less optimistic in the sense that they were about 65% of the sequela also registered at a higher risk in the covid group versus the control group.(14:25):So now it's very, very important for people to really know that this is really because we needed to do a two year study, we couldn't really enroll somebody in the study who had covid six months ago. They don't have a two year follow up. So this is a two year study. By necessity, we had to enroll people from the very first year of the pandemic, which meant that most of the people there or nearly all actually were the pre delta era, the ancestral strain or pre delta era and were non-vaccinated. So to the core of the question, how does this risk profile change with time? And my hunch is that a lot of things have changed. Obviously now we have vaccination, we have population level immunity. The virus itself has changed. We have antivirals, Paxlovid and others, but mainly Paxlovid and all of those are known to ameliorate the risk of not only acute disease but also chronic disease or the risk of Long Covid to various degrees.(15:24):But there's certainly we see in our work and other people's work, there is evidence of risk reduction in the risk of long-term sequelae or long-term consequences of SARS-CoV-2 infection. So that leads me to believe that the risk now or would be lower, but that's really a hypothesis. I don't have data to back this up. You asked me for data today for three year, I don't have it yet. We're thinking about it a lot. We're trying to work on it. I don't have it yet, but the hunch is that this is really, it's, it's lower now than a way it was.Clarifying the Role of Reinfection and Long CovidEric Topol (16:06):Right, right. No, that'll be really interesting to see. And I certainly agree with you as other studies, obviously none as large as what your data resources with the Veterans Affairs have suggested that the vaccines and boosters are providing some protection. Paxlovid, Metformin in a randomized trial, as you well know now, one of the papers of the many in top tier journals that you published was about reinfection. And this led to some confusion out there, which I hope that you'll be able to straighten out. I saw it as a dose response whereby if you have multiple re infections, the chance of you developing multiple of a long covid syndrome would be increased to some degree. Can you clarify that interpretation?Ziyad Al-Aly (16:57):This is exactly right. So a lot of people sort of interpreted it as we're trying to evaluate the risk of second infection versus the first, or whether the second infection is more mild or more severe than the first. That's not really the study question. So what we did, we sort of said that now we know a lot of people had a first infection that's already happened to these people. They cannot go back and erase it or do anything about it. They already had a first infection. What's the most important question for somebody who had a prior infection going forward? Does it matter to me or is it helpful to me to protect myself from the second infection? Right. So we designed the study and arguably designed a little bit was confusing to some people in the media. We designed the study to evaluate the risk of reinfection versus a counterfactual of no reinfection.(17:50):So basically if you have two people who have equal characteristics at baseline, everything equal, they had a first infection, one protected himself or herself from getting a second infection and the other one did not and then got a second infection. What are the outcomes in the person who did not get a second infection versus a person who got a second infection? And the results are very, very clear that a second infection or reinfection is consequential. It adds or contributes additional risks both in the acute phase, it can put even reinfection can put people in the hospital, can also result in some death that's very, very clear in our data and is very clear in other data as well and can also contribute risk of long. So I think the best interpretation for this is that for people to think that two infections are worse than one and three are worse than two, so two infections are worse than one and three are worse than two.(18:46):But we've learned a lot from this paper because I definitely agree and I've seen a lot of not the right interpretation for it. We discovered that America does not like counterfactual thinking. It's really hard to explain counterfactual thinking, but that's really what we thought about as the most important question to answer. It isn't really whether a second infection is really milder or more severe, and at first is more like if you were to do something about it, does it really help you to prevent yourself from getting a second infection or a third infection? For us to design the study to answer this specific question, we compared reinfection to no reinfection and we thought we wrote it very clearly still some headlines where, oh, these are comparing a second infection to a first infection, which that's was not our intent. We didn't really design this set this way.(19:42):As a matter of fact, we had a little bit of a hunch that it might be misinterpreted this way at the very, very last minute. In the copy editing stage, I inserted a sentence in the discussion that our results and our work should not be interpreted as a comparison of a second infection versus first, I hope the editor is not listening. I inserted this at the last minute in the copy editing stage in the limitation section to help people understand that this is not an evaluation or a competitive evaluation of the risks of the second infection versus the first, but more a second infection versus no second infection.Getting CovidEric Topol (20:21):Right, right. No, I'm so glad you clarified that because I think it's an important result and it has indeed. Everything else you've done been replicated. So now I want to ask you have, are you in Novid? Have you ever had Covid?Ziyad Al-Aly (20:38):Oh, I did have. I tried to reduce my risk and I did everything I'm supposed to do except that this June, about two months ago, I traveled and I got it while traveling. I think, I guess I was doing all the precautions that I could and I got it. I ended up having, although I'm young and I don't mind sharing, I got Pax Ovid because I got back slowly and I got over it. But that was my first, and it was only two months ago and I did my best throughout this pandemic to prevent it. But then travel is tricky because you are exposed a lot of people on the plane and it's tricky at the airport is very busy, crowded and it's very tricky. No,Eric Topol (21:27):Especially because people are not taking precautions anymore. And so you go to these crowded places with poor ventilation and very few people wear masks, and we still have all these people who are anti mask and that isn't helping either. So the next thing I was going to ask you about was you've done this remarkable work, a series of papers that have led the pandemic and in fact, you really have the only pulse on the United States data because outside of what you have in terms of all these electronic health records and longitudinal follow-up, we don't have any health system that has this capability. So we have relied on you and your team to give us these really critical readouts. What are you going to do next?Ziyad Al-Aly (22:20):We're very committed to understanding Long Covid. So we feel there is a lot of knowledge gaps that still need to be unpacked and understood, and we really, I feel committed to it. So we came to long covid because we sort of felt the voice of the patient advocacy groups at the very early phase of the pandemic saying at that time they were not so organized, but they were saying an up at pieces that we're having a problem here and somebody needs to look at it and somebody needs to evaluate it. We immersed ourselves in long covid, really inspired by the patient advocacy groups initially, and we feel connected to this. So that's, we're definitely committed to deepen our understanding of long covid. But having said that, I sort of feel that I do hope that our work inspire others that there is a lot of value in data, there are limitations. Existing data or big data is not without limitations. There are limitations in the data, but it can also unlock a lot of insights, especially in crises like the one we just experienced, the pandemic.Missed RECOVER Opportunities and Testing Treatments for Long CovidEric Topol (23:28):I think you have some extraordinary opportunities. So for example, when you found what previously was not appreciated for the data resource of the Veterans Affairs, the relationship between a medication protein pump inhibitors and kidney and cardiovascular diseases, I wonder for example, because so many people take metformin, would Metformin show protection from long covid within the Veterans' Affairs database as an example? Of course, maybe there are even some medications that are commonly used that offer a protective effect. I mean, you might be able to look at something like that because the data you have to work with in so many ways is massive and unprecedented.Ziyad Al-Aly (24:14):Well, yeah, I mean the scale of a data is really amazing. So it is really the largest integrated healthcare system in the US and it's really fully integrated. There's lab data, medication data, socio demographics, everything benefits data. Literally everything is in one place and there is opportunity to try to evaluate therapeutics effective metformin, other anti hypoglycemics, maybe GLP ones. And so there's a lot of these hypotheses that they, because the virus might reside in fat cells, there is this hypothesis that we just recently reviewed in a beautiful review in nature immunology, unlike the viral resistance hypothesis, so as a potential mechanistic pathway for long covid. So there are a lot of hypotheses around metformin and GLP one, and I think the VA environment or data environment is certainly good to test those, at least to help inform trials in this space. Now, there is already a trial on metformin, so that's done by David, but looking at it from another angle in the VA data would also, I think would add insight and would further contribute to the national conversation.Eric Topol (25:30):Right. I mean I think the Canadians, McMaster are starting a very large trial, Metformin with 5,000 participants. But I wonder if there were these drugs that are linked to mTOR and mitochondrial function enhancement, which as you said, not only was there an excellent review on the persistence of the virus in reservoirs, but also one that you know of well, bringing in the potential of mitochondrial dysfunction as a unifying theme. Now as we go forward, obviously the covid problem is not going away. We have this circulating virus in one form or another, one version, one strain or another over the years ahead. And we only know of one way to avoid long covid for sure, which is not getting covid in the first place. And at least we have some things that would help if you have Covid, like what you've already reviewed with Paxlovid. But the question is there's no treatment out there. And you have been of course helping as an advisor to the White House and WHO and the patient led collaborative. And the frustration out there is high because the big recover at NIH had over $1 billion and they have done really almost nothing in clinical trials. Imagine if you had 1 billion to work with. Can you comment about the fact that here we are, we're in September of 2023 and we don't even have one good clinical trial of a potential therapeutic.Ziyad Al-Aly (27:09):So this is enormously frustrating to me as well. It shouldZiyad Al-Aly (27:15):Yes, yes, yes. So no, we are definitely on the same page. So this is enormously frustrating to that. And three years into the pandemic, we still have, and I do remember when I see the white box that you put on your tweet and I think was recently illustrated in Fortune Magazine. There's three years into it. This is a full list of therapeutics for long covid and it's literally zero, nothing there. So it's very, very, very disappointing. And I do think that we want recover to succeed. That's really very, very important. We want recover to succeed. The patient community want also recover to succeed. And I think this really hopefully an invitation, all this what I think is a constructive criticism of recover, hopefully the recover folks will take it to heart and will sort rethink the approach and rethink the allocation of funds. In particular.(28:08):What really bothers me the most, and I've told them about this, I mean, as you know, I talked to multiple people in HHS and White House and all that. What really bothers me the most is that a lot of the money had been actually allocated to the observational arm to recover. And my argument to them is that actually we can produce the same. We actually not can we have produced all that evidence for peanuts two years ago. We need a study in JAMA to tell us that while long covid is characterized by fatigue and brain fog, I know that already, I already did that two years ago, an observational study. Well, we need interventional studies. What we need, most of the money should really be allocated to interventions, not really observational arm. And it's not too late to correct course. It's absolutely not too late to correct course. Well,Eric Topol (28:56):You're kind, but I'm afraid they've run out of money. And so I don't know they're going to get any more to do the trials, which are as very expensive to run. So it's not too late to do the trials, but unfortunately it's very hard to get the funds to support them. I thinkZiyad Al-Aly (29:14):There may be mechanisms for them to reallocate things, but also very importantly that we cannot, even if they reallocate this $1 billion to long covid, I think we need a longer term program and COVID should have a support that it should be. We argued that loco, which should have its portfolio at NIH, maybe not an institute and have a line-item funding so year there will be funds for long covid. Now we're told past F Y 25, fiscal year 25, there won't be additional funds for long covid. And that's really not how we should treat really the long-term consequences of SARS-CoV-2. And why is that the case? Why we ask why that's really will not only pay dividends to help us understand what long covid is and how to best treat it. It also can shed light into the other basket of infection associated chronic illnesses that I argue that we have ignored for a hundred years.(30:12):Again, COVID or SARS-CoV-2 is unique and it's not is unique because now we're in a pandemic and the scale of it is really big and all of that. But if you really think about it, there's actually a lot of viruses that have produced a lot of long-term effects that we've ignored their long-term consequences for a long time from the research perspective and also from clinical care. And that needs to be researched. So research on long covid or understanding along covid will help us with long covid, help us better understand the infection associated chronic illnesses. And three, also help us with pandemic preparedness. There is almost like a universal agreement that with climate change, with human encroaching on animal habitat, with human traveling so much more in the 2020 first century than in the 20th century, that the frequency of pandemics in the 21st century is likely to be higher than the frequency of pandemic in the 20th century.(31:06):So we're going to experience more pandemics in this century. We have to be prepared for them. This pandemic is not the first and unfortunately, unfortunately, it's not going to be the last. There's going to be another one in five years. In 10 years, in 20 years, we don't know. We cannot really predict these things, but it's almost certainly there're going to be one or more than one downstream and we have to be prepared for it. So I think we should not be shortsighted. I also argue that we already paid the price, the hefty price in this pandemic, more than 1.1 million deaths. We already paid the hefty price. We already paid a very, very dear price in this pandemic. Let's learn from it. Let's learn as much as possible from this pandemic. Let's learn to be able to help us for the next one.Post-Viral Syndromes Multiple Years OutEric Topol (31:47):Now having said, I want to underscore a point you made, which is it's not just this virus of SARS-CoV-2, the Myalgic Encephalomyelitis (ME/CFS) and many other viruses have led to a post-viral syndrome, which can be very debilitating. So yes, we can anticipate that not only do we have a burden that goes well beyond covid, but we may see this sort of thing of lasting debilitating impact of future pathogens. But to that mind, I want to ask you, because when I studied on the influenza 1918 and the polio epidemics, what I saw was that we saw many years later new things that had not been seen at two years or three years. So as you know, after influenza, Parkinson's showed up 15 years later and after polio, 30 years later, 40 years later, we saw the post-polio syndrome. So I hope within the Veterans Affairs you'll continue to look for things that we haven't even seen yet, which are kind of what I would say are the known unknowns that there could be further surprises to this problem. I don't know if you have a comment about that.Ziyad Al-Aly (33:09):We're cognizant of the prior observations, the historic observations that it took several, it took more than a decade for Parkinson's to show up after the flu. And there potentially could be latent effects of viruses. Things that we're not seeing now, we still don't know because obviously the whole pandemic is in its fourth year. So we don't have 10 year follow up, but we are sort of building our systems here to look at five years and look at 10 years with an eye that if there are latent effects of SARS-CoV-2 infection, we want to be able to see it and characterize it and understand it and hopefully figure out how to best prevent it and then treat it. So we're very, very cognizant of the fact that viruses, some viruses can have very latent manifestations. For example, EBV and multiple sclerosis, it doesn't show up immediately. It shows up way down the road. Epstein Barr virus and multiple sclerosis. A lot of viruses, not one, again, SARS-CoV-2 is not unique. There are a lot of viruses produce long-term conditions and they have different timing when they show up. And so we're very, very interested in this and certainly are building our data systems here to look at five years and 10 years.The Lack of Public Regard for Long CovidEric Topol (34:20):Yeah, that's perfect. I knew you would. I just wanted to make sure I touched on that with you because you don't miss a beat. Now, the problem I see still today, Ziyad, is that there's lack of regard, respect, acknowledgement for long covid despite your phenomenal work. Despite that there's 60 million people around the world and then still more as infections again are on the uprise, there's people out there saying that these are malingers, that there's no such thing. I can't even post things about Long Covid on social media like Twitter/ X because I get all this pushback that it's made up and it's a hoax and this is just unnerving because we both know people who have had, they were athletic and now they're either wheelchair or bound to bed. I mean, this can be so people are suffering. What can you say about the fact that there are these people who are trying to dismiss long covid after all the work that you have done along with so many other researchers around the world to nail this down as a very big issue?Ziyad Al-Aly (35:36):So I definitely think it's a big issue. It's really unfortunate that in the US and actually some other parts of the world, that the whole pandemic has been politicized. And it's really sad to see, I mean, not as much as you, but I get some of the pushback on Twitter. And even sometimes when we publish a paper, sometimes people find my email, I don't know how they find my email. They find my email, I get what I call them nasty grams. Really sort of a very, very unpleasant emails, very unpleasant emails. And I just delete and I don't respond. So it's really hard to understand. It's really hard to understand. But there is a lot of misinformation, a lot of disinformation, a lot of politicization of the pandemic, a lot of politicization of vaccines and their side effects. And it's almost polluting the national conversation.(36:30):And it's toxic because these things are, this is not free speech. This is actually speech that harms other people. There are people that feel disenfranchised, that feels sort of the feel that their illness is not recognized. Or some people refer to it as gaslighting condition is being gaslit by this toxic discourse. And that's really unfortunate. But I wish I have a very clear solution or very clear understanding of how to address this. It's something that baffles me. And because of some of the stuff that I experienced, I sort of classify as almost toxic. It's reallyEric Topol (37:09):Very, again, you're being kind because it's, or I mean you're not. I think it's so dreadfully toxic. It's disgusting, despicable. Now I'm disconcerted because for example, the last time we had a state of the Union address by the president, he said, the pandemic's looking good. I've never heard our president say about long covid and our other leaders in our country to acknowledge how vital this is. It's great that we had the N I H to allocate significant funds, but may be that a lot of that unfortunately has been wasted. But I think we can do much better in getting the point across that this is a really big deal, that so many people, their lives have been changed. We don't have a remedy in sight. Only a very limited number of people, as you've published, really fully recover, particularly if they've had a severe case. So I hope that in the future we will have a better consensus among the spokespeople leadership that acknowledges the breadth and depth and seriousness of this problem. So the last thing I want to ask you about is you have had a record of prolific work in this pandemic, and I want to know what your daily routine is like. Do you sleep? What do you do?Ziyad Al-Aly (38:46):We feel very committed to this. So we are really working constantly almost all the time. And definitely I do sleep and I do go to the gym and I try to maintain some healthy balance, but I also work on Saturdays to try to write papers and move things forward. We're a small team, but we feel very driven to keep moving the ball forward long. And really honestly, thanks to the patient community that has supported us from day one actually inspired us and supported us from day one. So feel very connected to this cause and feel, want to move it forward. And it's a lot. But again, kudos to my team. They're amazing and it's a small team, but they're really, really absolutely, absolutely amazing people. And you doEric Topol (39:28):A lot of kudos to you too, because you've been leading this team and you've illuminated Covid from the US standpoint, no group, no less for the world. And these studies have been one after another. Just really an extraordinary and seminal paper. So in closing, Ziyad, I want to thank you for what I consider heroic efforts. You and your team, you have lit up this whole space of covid for all of us, and it's superimposed on great work that people didn't know about that you were doing. The Washington University of St. Louis, one of the leading academic medical centers in the country and the world as well as the Veterans Administration should be so proud of you and your colleagues for this work. This is tireless work. I know every time you submit a paper and every time you go through all the peer review and the revisions and the resubmission, and then you've done it all through these years of the pandemic, and I know you'll continue as well. So thank you for this indefatigable effort, which has really been extraordinary and I look forward to keeping up with you and all the future efforts, and I know you'll be on it for years to come.Ziyad Al-Aly (40:51):Well, thank you. Thank you. Thank you for having me. And again, thanks also for all your effort in this pandemic communicating science to elevating science and communicating to the wider public now, all your wonderful, amazing, gigantic prior contributions. So thank you for your contribution to America and the world, and especially being the communicator in chief throughout this pandemic.Eric Topol (41:12):Oh, you're too kind. We'll talk again. I hope soon and great to be with you today. Thank you.Ziyad Al-Aly (41:18):Thank you.If you prefer to watch the whole convo by video, here Is the link Get full access to Ground Truths at erictopol.substack.com/subscribe

Eric Topol (00:00):Hello, this is Eric Topol, and I'm thrilled to have a chance to have a conversation with Magdalena Skipper, who is the Editor-in-Chief of Nature. And a historic note. Back in 2018, she became the first woman editor of Nature in its 149 years, and only the eighth editor of all times. Having taken over for Philip Campbell, who had been previously the editor for 22 years, we're going to ask her if she's going to do 22 or more years, but we're going to have a fun conversation because there's so much going on in medical publishing, and I think, you know, that Nature is the number one cited science journal in the world. So, welcome, Magdalena.Magdalena Skipper (00:41):Thank you very much. Real pleasure to be here and chatting with you today, Eric. Thank you.How COVID-19 Affected NatureEric Topol (00:47):Well, you know, we're still, of course, in the pandemic world. It's obviously not as bad as it had been, but there's still things going on with new variants and Long Covid, and it's not, the virus isn't going away. But first thing I wanted to get into was how did Nature handle this frenetic craziness? I mean, it was putting out accelerated publications on almost a daily or weekly basis and putting out like a speed, velocity of the likes that we've not seen. This must have been really trying for the whole crew. What, what do you think?Magdalena Skipper (01:29):It was! And, you know, the first thing I, I think I will recognize two things at the same time. So the first one, as you say, at a time, such as the pandemic, but actually at any point when there is a, a new health emergency that is spreading, especially something as unknown, as new as, as it was the case with SARS-CoV-2. And of course, in the beginning, we really knew nothing about what we were facing if speed is of the essence, but equally what's truly important is of course, the rigor itself. So that combination of needing to publish as quickly as possible, but at the same time as rigorously evaluating the papers as possible, that was actually quite a challenge. And of course, you know, what we sometimes forget when we talk about, well, researchers themselves, but also editors and publishers is of course, as individuals, as human beings.(02:33):They are going through all the trauma, all the constraints associated with various lockdowns concerns about the loved ones, perhaps those ones who are in the care. You know, in many cases of course there would've been the elderly who are individuals would've been concerned by or indeed children, because of course, schools in so many places were. And all the while, while we were dealing with these very human, very ordinary daily preoccupations, we were very focused on the fact that we had a responsibility and a duty to publish papers and evaluate them as quickly as possible. It really was an extraordinary time. And, and you know, one other thing I should emphasize is, of course, it's not just the manuscript editors who evaluate the research, it's the reporters on my team as well who are going out of their the way to find out as much information to report as robustly, find as many sources to, to interview as possible.(03:44):And, and, you know, I also have to mention colleagues who work on production side of nature actually make Naturehappen, be published online on a daily and then of course weekly basis. And literally from one week to the next all our operations had to be performed from home. And it's really remarkable that the issue was not late. We published the issue, just as you know, from as lockdowns came in. And as it happens, the production side of Nature is mainly based in, in London. So most of that team effectively found themselves not being able to go to the office effectively from one day to the next. So it really was an extraordinary time and, and a time that as I said was, was a time of great responsibility. But looking back on it, I'm actually incredibly proud of, of my team, what, what they achievedEric Topol (04:47):Did they hold up? I mean, they hadn't, they didn't get burnout from lack of sleep and lack of everything. Are they still hanging in there?Magdalena Skipper (04:55):So they are hanging in there. You'll be glad to hear. But I think, very importantly, we were there for one another insofar that we could be, of course, we were all at home remotely. We were not meeting, but we had virtual meetings, which were regular of course in as a whole team, but also in, in subgroups as we sub-teams, as we worked together, that human contact in addition to of course, loved ones and families and friends, that human contact in a professional setting was, was really, really necessary. And clearly what I'm describing was affected all of us one way or another. Sometimes there is a tendency not to remember. That also applies to editors, publishers, and of course researchers themselves. I mean, very clearly they were at the forefront of the issue facing the same problems.Nature and Challenge of Generative A.I.Eric Topol (05:57):Well, a new challenge has arisen, not that the pandemic of course has gone away, but now we have this large language models of AI, Generative AI, which you've written editorials at Nature, which, of course, is it human or is it the machine? What do you think about that challenge?Magdalena Skipper (06:19):Well of course, you know, the way I like to think about it is AI, of course, broadly is, has been around for a very long time, a number of decades, right? And steadily over the last several years, we have seen AI emerge as a really powerful and important tool in research right across a number of disciplines. The reason why we are all talking about AI right now, and I really think all of us are talking about AI all the time, is, of course, specifically the emergence of generative AI, the large language models that, that you just mentioned. And they sort of burst onto the scene for all of us really last year in the autumn with chat GPT and GPT-4 and so on. But it's important to remember that, of course, when we talk about AI, there are other models, other approaches, and machine learning in general has been creating quite some revolution in research already.(07:36): You know, probably the best example that will be familiar to many of the  listeners was of course Alpha Fold which, you know, Nature published a couple of years ago and, and has been really revolutionized structural biology. But, of course, there are many other examples which are now becoming developing much more rapidly, becoming much more, I would say, commonplace in, in research practice. You know, not just predicting structure from sequencing from sequence. And I say just so flippantly now, of course, it was such and it continues to be such an incredible tool. But of course now we have AI approaches, which actually suggest new protein design, new, new small molecule design. We've had in the last couple of years, we've had identification of new potential antibiotics that are effective against bacterial strains that have otherwise been resistant to any known antibiotics.(08:48):And, and of course, it's not just in biomedicine. Material science--I think it's very helpful, hopeful when it comes to, to AI tools as well. And then, and of course, generative AI indeed helps us in some of these contexts already. But I think your question perhaps was more focused on the publishing, the communication, the sort of output of, of research, which of course is also very important. In some way. The reason why I answered, I began to answer the question the way I did, is because I'm actually very excited about harnessing the power of AI in augmenting research itself. Helping navigate enormous data sets generate hypotheses to be tested finding new ways to advance projects. I think that's a very exciting opportunity. And we're just beginning to see the first applications of it.(10:04):Now, in terms of publishing you referred to some editorials that we wrote about this. And right at the beginning of the year, there was a flurry of excitement associated with the ability of generative AI to indeed generate text. There were some manuscripts which were published in journals that were co-authored by Chat GPT. I I even believe there was an editorial which was co-authored by Chat GPT. So in response to that, we felt very strongly that, that clearly there was a need to, to come out with a, a clear position, just as in doing research, we see AI tools as tools to support writing, but clearly they don't have the ability to fulfill authorship criteria. Clearly, they cannot be authors. Clearly, they must only remain as tools supporting researchers and individuals writing and communicating their research.(11:23):And so we, we wrote a very clear editorial about this, essentially summarizing what I just explained and asking the community to be transparent about how AI tool has been used, just as you would be transparent about your methodology, how you have arrived at the results that you're reporting and, and results that support your conclusions. So for us, it's a relatively simple set of recommendations. As I say, we ask for transparency. We understand it can be a tool that can be used to help write a paper. What we also ask at this stage that generative AI tools are not used to generate figures or images in papers, simply because there are a number of outstanding copyright issues, a number of outstanding privacy issues, they remain unresolved. And for as long as they remain unresolved, we feel it's not an appropriate application of these tools. So that's our editorial position.Eric Topol (12:42):Yeah, no, that's very helpful. I mean, where do you think, if you write a manuscript and then you put it into let's say GPT-4 and say, please edit this, is that okay? Or is that something that, and it's acknowledged that the paper was written by us researchers, but then we had it tweaked by chatbot or is that something that it wouldn't go over too well?Magdalena Skipper (13:10):Well, my preference, and actually what I would hope is that if you were writing this paper and then you felt the need to put it through a chatbot as you just put it, although I find it hard to imagine that you would find no need for that,Eric Topol (13:29):I wouldn't do it. But I know there's people out there that are working on it.Magdalena Skipper (13:32):Yeah, absolutely. But then I would hope that the last pass, the final word, would rest with you as the author. Because, of course, if you are using a tool for whatever it is that you do, you want, at the end of the day to make sure that what that tool has returned is aligned with what you intended that you perform some kind of a sense check. We, of course, all know that although GPT-4 has less of a tendency to hallucinate, so to essentially come up with fabricated sort of statements and, and reality, if you like, it remains an issue. It can remain an issue. And very clearly any, any scientific communication has to be rooted in facts. So, in the scenario that you propose, I would hope that if a researcher felt compelled to run the manuscript through a chatbot, and for example, one consideration may for an individual whose English is not their first language, who feel may feel more comfortable with a sort of support of this kind. But in the end, the final check, the final sign off, if you like, on that manuscript before submission would need to come from the researcher, from the corresponding author, from the writing group. and indeed assistance from a chatbot would need to be disclosed.Eric Topol (15:14):For us. Yeah, I mean, it's really interesting because you can almost foresee the shortcut of having to go get all the references and all the links, you could say, you know, please insert these, but you better check them because they may be fabricated Absolutely. It's going to be really interesting to see how this plays out and the difficulty of detecting what is written by a large language model versus a person.Nature and PreprintsNow another topic that I think is really in play is the preprint world and publishing via preprints. And as you know there's been Michael Eisen and the whole idea of how things would move with his journal eLife. And you will remember when you and I were together at a conference. I organized Future of Genomic Medicine many years ago at the kind of dawn of life science preprints. And some people in the audience sai, “what's a preprint?” Right? Nobody else asks about that now. It’s come a long way over this decade. And where do we go with this? Should journals like the top journals in the world like Nature require a paper to be vetted through the pre-print mechanism? Where is this headed, do you think?Magdalena Skipper (16:40):Yeah, it's an excellent question. And, and you know, by the way, I have such wonderful memories from, of that conference. I think this must have been like 11 years ago or something like that. It was a long time ago. And I actually remember presenting this, this vision of a rather radical vision of, of the future of publishing. And here we are in the future as compared to then, and we have moved relatively little by comparison to where we were then. But back to your question. So, you know, the first thing to say is that, of course, just as a reminder, preprints have been around for more than two decades now. And, and of course they initially were really spearheaded and advanced by the physical sciences community. archive itself is, as I say, more than two decades old. So, you know, for us at Nature as a multidisciplinary journal where of course, we've been publishing in the physical sciences since the very beginning of our existence as soon as preprints first emerged in those communities, we realized that we could coexist very harmoniously as a journal peer-review based journal with preprints.(17:59):So when initially biological sciences community embraced them and bioRxiv was established, and then of course, many other archives and then subsequently actually really spearheaded by Covid, the medical and clinical community began to embrace preprints. in many ways, for us, that was nothing new. It was just an extension of something that we worked with before. Although our own our own policies have evolved. So, for example, during the pandemic we actually mandated deposition of papers that were submitted to us that were Covid related. We mandated the deposition in a preprint server. The authors had the choice which server they deposited, but we wanted those manuscripts to be available to the community for the scrutiny as soon as they were finalized, as soon as they were actually written. So while we were reviewing them again as quickly as rigorously, but as quickly as possible, the preprint was already available for the community just before the pandemic.(19:17):As it happens, we also took a step forward with our policy. So previously, let's just say we were completely fine with preprints. We saw preprints as compatible with submission to, to Nature, and for that matter to the other journals in the Nature Portfolio. But actually just in the year before COVID started, we decided to actively encourage our authors to deposit preprints. We could see that preprint sharing had great advantage. You know, the, the usuals of advantages, which are often listed first are of course ability to make that primacy claim, make a stake that, that you have been working on something and, and this is your project. You have a set of results that you are ready to communicate to, to the community at large. And of course, another very important one is that sort of community and, and almost public form of peer review and, and ability to comment.(20:30):And incidentally, I remember as you know, my, my history as an editor very well. We've known each other for a long time. I remember when the genomics community, which is sort of my, my background is sort of my old hat, if you like, that, that I used to wear when the genomics community began to embrace preprints especially the population and evolutionary genomicists really embraced this idea that this was like a group peer review. And the authors of those preprints were very grateful to the community for improving the papers before they were submitted to journals, or sometimes that sort of community review was going on while a paper was being considered at a journal. And we, as editors actually encouraged sort of formal submission of these reviews, if you like, I mean, formal maybe is the wrong word, but we were saying that we would take those comments into account when evaluating papers.(21:38):So there has been an interesting evolution that more and more disciplines, more and more fields have embraced preprints as a way of disseminating information. Preprints service themselves have also grown and matured in the sense that there is now realization that, for example, clinical preprints need a higher degree of scrutiny they're posted on a preprint server than maybe let's say theoretical physics or theoretical biology preprints. So overall all communities collectively have grown and matured. Where are we going with this? I mean, who knows? I was predicting 12 years ago you know, a bit of a different, more advanced future today. It's very difficult to predict the future. I do think, however, that what we are seeing today, that sort of hand in glove coexistence of preprints with journals, with peer reviewed papers is going to continue into the future. And I think actually that's a really valuable and interesting combination. So it's a great development to see and great to see that communities right across disciplines have really embraced this.Eric Topol (23:11):Yeah, I think it does complement, obviously the traditional peer review of a few expert reviewers with, you know, could be hundreds if not thousands of people that weigh in on, on a pre-print. So yeah, it's fascinating to see. And it's, I still remember the vision that you portrayed for it, and how we we're not quite there yet, but I'm sure there'll be further evolution.Women in Science: Where Do We Stand?Now, another area that I think is particularly good to get your input, because you're a woman in science, as you mentioned, you know, grounded obviously in genetics and genomics, and here you are, one of the most influential women in science at a time when there's been a reckoning that women in science have been shortchanged historically, I mean, for hundreds of years. Do you see that this is starting to get better? Are there palpable signs that we're finally getting kind of equal rights here? Or are we, is it, is it just still a long fight ahead?Magdalena Skipper (24:20):So the, the optimist in me and, and I should say, you know, my, my glass, my glass is always half full. The optimist in me says that it is getting better, but the realist in me has to add immediately that the changes too slow. It really is too slow. We do see many more women prominently able to make the contributions that they should, they can, and they should make to whatever discipline whatever aspect of the research community and beyond they wish to, to make. I still think it costs them too much. I still think we don't appreciate and support women sufficiently.(25:23):Maybe we have moved on the bottleneck in the, in the pipeline a little bit further, towards more seniority. But we still, we still don't sufficiently support women. As I say, we, I think we still default to an expectation that successful women in science in research more broadly will somehow emulate how success has looked in the past. And that's a shame, that's a shame not just for those women who are trying to come in and make a difference, but it's a shame for all of us because it means that we are denying diversity in that picture of success. Yes. So yes, I think, I think that we have seen many changes, but I think the change is not happening fast enough.Eric Topol (26:23):Yeah. One of the things that I've noticed since of particular interest in AI is that the very profound imbalance of researchers, the gender imbalance there is just, you know, I'm not even sure if it's 10% women researchers in AI, so that has to be changed. And so this, there's so many things that are holding us back, but, but that's certainly one of, of many.Magdalena Skipper (26:49):Absolutely. And, and, and if I can just add, there are some outstandingly influential female researchers in the AI field, as you say, they are just outnumbered. Yes. , I think not given the opportunity to, to fully blossom, if you like, considering their capabilities and, and their contributions already.Eric Topol (27:11):You know, it's so true. I just interviewed Melanie Mitchell from the Santa Fe Institute, and I work with Fei- Fei Li. And when I, when Fei-Fei Li and I spoke some months ago about a book (Genius Makers) that Cade Metz, the New York Times journalist had written, and I say, why didn't he bring up or emphasize the role of any women in the whole book . Yes--who work in A--I mean, she, she obviously was, was did not take that particularly well, and as did I.Too Many Nature Portfolio Journals?So one of the other areas that I think you already touched on, which is separating Nature, the flagship journal from the Nature Portfolio of, I don't know what it's up to now, 200, 300, I'm not sure how many journals are. So do you, do you have to over oversee that? Do you have input on that? Because what I worry about is, you know, people quote a Nature journal and it may not be, you know, at that level that you would be proud of. What, what are your thoughts about this endless proliferation of the nature portfolio?Magdalena Skipper (28:17):Well, I, I'm, first of all, I'm not sure if it's endless, butEric Topol (28:20):Oh, that's good. .Magdalena Skipper (28:22):So, so  let me, I think in your question, you touched on a number of things. So first of all, a clarification. So my role is as Editor-in-Chief of Nature, and of course, that is my main focus. there is another aspect to my role, which is Chief Editorial Advisor for the Nature Portfolio. So in that sense each of the journals within the Nature portfolio has its own chief editor. but by virtue, I guess, of my seniority, and also by virtue of multi-disciplinarity of Nature I have this advisory role to my colleagues in the other journals. I like to think about the Nature Portfolio as an ecosystem, actually. And it's an ecosystem, like any ecosystem. It has different niches, each of which fulfills a different role. Some of them are bigger, some of them are smaller, some of them are very specialized, others are more general.(29:22):And I think you know, working with researchers for many years as an editor now, I can see benefits to having that sort of almost an ecosystem type approach to publishing. You know, for example, we mentioned already earlier that in my previous sort of incarnation as an editor, my focus was on genomics especially in the context of human genomics. of course starting from the Human Genome Project, these were very large or have, where, why, why am I using past tense? They are, to this day, very large collaborative projects involving many different labs, many different approaches these days that they're not just focused on genomics, but of course other omics go hand in hand with them. So when a project comes to fruition, when, when it comes to be published, there are many different pieces that need to be communicated, many different papers of different sizes of different value.(30:32):And for example what value maybe is the wrong word of different utility? So, for example, there may be a flagship paper that is published in the pages of my journal of Nature, but there may be papers that specifically described development of methodology that was part of the same stage of the project. And those papers may be published in Nature Methods, which is part of the Nature Portfolio. There are other journals that are part of Nature Portfolio, which have different editorial bar. And so, you know, one example is Scientific Reports, which is a journal which does not require conceptual novelty in the papers that it publishes. Of course, it requires rigor and, and robustness in the papers that it publishes, like every journal should. But there is utility in publishing papers in a journal like this.(31:36):There may be replications that are published there that further add further evidence to support conclusions that are already well known, but nevertheless, they're useful. I should however, add that in Nature itself, we also publish replications, right? There are different degrees of influence and impact that, of course, different studies be there, replications or not that can carry. So, that will be my way of conceptualizing the Nature Portfolio. and, you know, coming back to your, to your comment that it seems like it's endless. I think well, nothing, nothing is endless. Of course. Nothing, nothing, right, grows forever. I do think that we have in the launches within the portfolio, we have been able to capture and at the same time serve an interesting evolution in the research ecosystem itself. So the final comment I will make on this is, if you look at some of the more recent launches in the portfolio, they've been what we like to call thematic journals, such as, for example, Nature Food or Nature Water.Eric Topol (33:10):Right?Magdalena Skipper (33:10):And here we are really capitalizing on that multi-disciplinarity of these emerging themes that, especially in the context of sustainable development goals, have acquired their own identity. They don't belong to one discipline or another discipline. And, and so these journals, they're new journals, relatively new journals, some of them very new Nature Waters is, is quite new, but they provide a focal point for researchers who come together to solve a particular set of problems from different disciplines. And I think that's an interesting function in, as I say, for the community.What About the Paywalls?Eric Topol (33:53):Yeah, there's no question some of the newer journals and their transdisciplinary mission --they're needed and they become extremely popular and well -cited very quickly to prove that. So along that line obviously the public is all fired up about paywalls and you know, and obviously for Covid, there was no paywalls, which is pretty extraordinary. Do you see someday that journals will have a hard time of maintaining this? I mean, you have what I consider an extraordinary solution, which is the ReadCube postings anyone can access, you just can't download the PDF, and I wish authors would always routinely put that out there because that would solve part of the problem. But do you think we're going to go to a free access that's much more wide, perhaps even routine, in the years ahead?Magdalena Skipper (34:52):So certainly open access as in ability to access a manuscript, published manuscript without any payment or barrier associated with a Creative Commons license is something that is advanced as a, as a preferred future by many researchers, by many funders. and for that matter, actually many publishers as well. You know, let me make one thing very clear. As an editor, I would love as many people as possible to read the papers that I publish in my journal.Magdalena Skipper (35:30):That should go without saying. Sure. at the same time, publishing papers, of course, is associated with a cost, and, and that cost has to be somehow covered. In the old days it was exclusively covered by library subscriptions or site licenses or personal subscriptions. Now the focus is shifting. And of course, Nature itself as well as the other research journals such as, for example, Nature Medicine or indeed Nature Water, as I mentioned before are what we call transformative journals. So effectively we are hybrid journals that advocate for open access. So today, when you submit a paper to Nature, you can publish under the traditional publishing model, or you can choose to publish open access, which is associated with an article processing charge. That should, in my view, be part of your costs of doing research, because after all, I'm a firm believer in the fact that publishing your research should be seen as part of doing research, not sort of an add-on.(36:47):Now, I'm glad you mentioned read Read Cube and this functionality that we call shared it. We developed it actually quite some years ago. I would say at least a decade ago. it remains curiously underappreciated. Yeah. I just don't understand it. Yeah, exactly. And, and we, we inform the authors that they are free to use that link. And, and just to clarify, it's a linked as you exactly as you explained to an online version of the paper. It's the final version, the record version of the paper. You can't download it, but you can share that link. Anyone can share that link once they have it Infinite number of times. So it's not like the link expires, or it's a, a finite number of, of that it has a number of finite number of uses in addition to that nature.(37:49):And for that matter, the whole of Springer Nature is part of Research4Life. Now, that's an organization that provides free access to all content from publishers. And Springer Nature is not the only publisher that's part of Research for Life that provides full access to all of our content in the countries which are designated as low and middle income countries by the World Bank. So that we've been part of that. And, and previously for many, many years, in fact, decades, again, that is curiously underappreciated, including in the low and middle income countries. So, you know, recently had an opportunity to do some visits in Africa. And my, my take home message there was, if there is one thing that you remember from our conversation or from my presentation, please remember about Research4Life.Magdalena Skipper (38:52):Because that content is freely available if you follow, if you go to our content through Research4Life. And incidentally, there's also training, which is available there. So part of Nature portfolio in addition to journals, we have Nature Master classes, which is training for researchers. And that is also completely freely available in those countries. So there are a number of approaches to, to getting content open access is definitely growing, but there are those other ways to gain access to content which is not open access at the moment.Eric Topol (39:33):I'm really glad you reviewed that because a lot of people who are going to be listening are going to really cue into that. Now the last question for you is, you know, it's not just every Wednesday, 51 or whatever, 50 weeks a year, that you're getting the journal ready, but it's every day now that you're putting out stuff and on the Nature website. Features that are by the way, free or full access and many other things to keep Nature out there on a daily, if not minute to minute basis. So this is really a big charge to, you know, do this all so well. So what keeps you up at night about Nature is this, this must be a very tough position.Magdalena Skipper (40:28):So the first thing I would say that is that of course it's, it's not me. I'm just the person here talking to you representing Nature. I have an outstanding team.Eric Topol (40:44):I've met them, and they're amazing.Magdalena Skipper (40:46):And it's really them who are making it possible on a minute by minute, certainly day by day basis. And so the reason why I sleep relatively well is thanks to them actually, okay,Eric Topol (41:00):. Okay.What Keeps You Up At Night?Magdalena Skipper (41:01):But more, but more broadly. and this is a thought which is bigger than Nature itself. What actually keeps me up at night these days is the rather difficult light in which science and research is portrayed these days increasingly.Magdalena Skipper (41:27):And I think it's very unfortunately being to support other goals and other ends forgetting about the fact that science is an ongoing process that science takes steps back when it needs to revise its position, that it still continues to be true, that s science progresses through self-correction. Even if that self-correction doesn't happen overnight, it takes time to realize that a correction is required, takes time to evaluate judiciously that correction is required and what kind of correction is required, right? These are the things that of course, you and I know very well. But the, sometimes if for individuals who are not close to the process of how science research fact-based discovery is conducted, if you just look at information on social media or in general media, you may walk away with an impression that science is not worth paying attention to that science is in some deep crisis.Magdalena Skipper (43:04):And I think that's, that's a shame that that's a picture that we have other things that need other things in science, in research that need correcting, that need sorting out. Of course, we mustn't forget that research is done by humans and, and after all it is human to air. But overall, that's actually something that keeps me up at night. That overall, I really hope that those of us who are engaged in one way or another within the research enterprise, we can continue to advance the right kind of image that it's not perfect in some artificial way, but actually, at the same time, it's the only way that we can move forward. We can understand the world around us, and we can wake, make the world around us better, actually.Eric Topol (44:11):Yeah. I'm so glad you've emphasized this because just like we talked earlier about distinguishing between human and AI content generated here, we have science and anti-science blurring facts, blurring truths, and basically taking down science as a search for truth and making it trying to, you know, obscure its mission and, in many ways, we, we saw it with not just anti-vax, but it's much bigger. The political motives are obvious extraordinary, particularly as we see here in the U.S. but other countries as well. So I almost didn't hit you for that question, just because it's so profound. We don't have the answers, but the fact that you're thinking about it tells, tells us all a lot. So Magdalena, this has been a joy. I really appreciate all your candid and very thoughtful responses to some of these questions.(45:09):Some of them pretty tough questions I have to say. And I look forward to our conversations and chances to visit with you again in the future. And congratulations again on taking on the leadership of Nature for five years now-- I believe just past your five-year anniversary now. You could say that's small out of 155 years, but I think it's a lot. particularly since the last few years have been, you really challenging. But to you and your team ultimately –-major kudos. I'm on the Nature website every single day. I mean, even, I when I’m on vacation, I'll be checking out the Nature site. So you can tell that I think so highly of the its content and we'll look forward to future conversations going forward.Magdalena Skipper (45:52):Thank you very much. Thank you very much, Eric. It's always a pleasure to talk to you. Thank you. Get full access to Ground Truths at erictopol.substack.com/subscribe

Transcript Eric Topol (00:00):This is a real great opportunity to speak to one of the most impressive medical informaticists and leaders in AI in the United States and worldwide. Dr. John Halamka, just by way of background, John, his baccalaureate in Stanford was at U C S F/Berkeley for combined MD PhD trained in emergency medicine at U C L A. He went on to Harvard where he, for 20 years was the Chief Information Officer at Beth Israel Deaconess. And then in 2020 he joined Mayo Clinic to head its platform to help transform Mayo Clinic to be the global leader in digital healthcare. So welcome, John. It's so great to have you. And by the way, I want to mention your recent book came out in April, one of many books you've written, redefining the Boundaries of Medicine, the High Tech High Touch Path into the Future.John Halamka (01:00):Well, a thrilled to be with you today, and you and I need to spend more time together very clearly.Eric Topol (01:06):Yeah, I really think so. Because this is the first time we've had a one-on-one conversation. We've been on panels together, but that's not enough. We've got to really do some brainstorming, the two of us. But first I wanted to get into, because you have been on a leading edge of ai and Mayo is doing big things in this space, what are you excited about? Where do you think things are right now?John Halamka (01:35):So you and I have been in academic healthcare for decades, and we know there's some brilliant people, well-meaning people, but sometimes the agility to innovate isn't quite there, whether it's a fear of failure, it's the process of getting things approved. So the question of course is can you build to scale the technology and the processes and change policies so that anyone can do what they want much more rapidly? And so what's been exciting over these last couple of years at Mayo is we started with the data and we know that anything we do, whether it's predictive or regenerative, starts with high quality curated data. And so by de-identifying all the multimodal data of Mayo and then working with other partners around the world to create a distributed federated approach for anyone to train anything, suddenly you're empowering a very large number of innovators. And then you've seen what's happened in society. I mean, culturally, people are starting to say, wow, this ai, it could actually reduce burden, it could democratize access to knowledge. I actually think that yes, there need to be guidelines and guardrails, but on the whole, this could be very good. So here we have a perfect storm, the technology, the policy, the cultural change, and therefore these next couple of years are going to be really productive.Implementing a Mayo Randomized AI TrialEric Topol (02:59):Well, and especially at Mayo, the reason I say that is not only do they recruit you, having had a couple of decades of experience in a Harvard program, but Mayo's depth of patient care is extraordinary. And so that gets me to, for example, you did a randomized trial at Mayo Clinic, which there aren't that many of by the way in AI where you gave E C G reading power of AI to half the primary care doctors and the other half you didn't for determining whether the patients had poor cardiac function that is low ejection fraction. And now as I understand it, having done that randomized trial published it, you've implemented that throughout the Mayo Clinic system as far as this AI ECG support. Is that true?John Halamka (03:56):Well, right, and let me just give you a personal example that shows you how it's used. So I have an SVT [supraventricular tachycardia] , and that means at times my resting heart rate of 55 goes to one 70. It's uncomfortable. It's not life-threatening. I was really concerned, oh, may I have underlying cardiomyopathy, valvular disease, coronary artery disease. So Paul Friedman and Peter Newsworthy said, Hey, we're going to take a six lead ECG wearable, send it to your home and just record a bunch of data and your activities of daily living. And then we buy 5G cell phone. We'll be collecting those six leads and we'll run it through all of our various validated AI systems. And then we'll tell you based on what the AI suggests, whether you're at high risk or not for various disease states. So it says your ejection fraction 70%. Oh, good. Don't have to worry about that. Your likelihood of developing AFib 3% cardiomyopathy, 2% valvular disease, 1%. So bottom line is without even going to a bricks and mortar facility here, I have these validated algorithms, at least doing a screen to see where maybe I should get additional evaluation and not.Eric Topol (05:12):Yeah, well see what you're bringing up is a whole other dimension. So on the one hand that what we talked about was you could give the primary care doctors who don't read electrocardiograms very well, you give them supercharged by having a deep learning interpretation set for them. But on the other, now you're bringing up this other patient facing story where you're taking a cardiogram when somebody's perfectly fine. But from that, from having deep learning of cardiograms, millions of cardiograms, you're telling what their risks are that they could develop things like atrial fibrillation. So this is starting to span the gamut of what the phase that we went through or still going through, which is taking medical images, whether it's a cardiogram or a scan of some sort, and seeing things with machines that humanize really can't detect or perceive. So yeah, we're just starting to get out of the block here, John. And you've already brought up a couple of major applications that we were not even potentially used three, four or five years ago that Mayo Clinics leading the charge, right?The Power of Machine EyesJohn Halamka (06:26):Well, yeah, and let me just give you two quick other examples of these are in studies now, right? So they're not ready for active patient use. The animate GI product does an overread of endoscopy. And what we're finding is that the expert human, I mean anywhere in the world, expert humans miss about 15% of small polyps. They're just hard to see. Prep may not be perfect, et cetera. The machine misses about 3%. So that's to say a human augmented with overread is five times better than a human alone pancreatic cancer, my father-in-law died about 11 years ago of stage four pancreatic cancer. So this is something that I'm very sensitive about, very often diagnosed late, and you can't do much. What we've been able to see is looking at pancreatic cancer, early films that were taken, abdominal CT scans and these sorts of things, algorithms can detect pancreatic cancer  two years before it is manifested clinically. And so here's the ethical question I'll pose to you. I know you think about a lot of this Scripps Mayo, UCSF, Stanford, we probably have thousands and thousands of abdominal CTs that were read normal. Is it an ethical imperative as these things go through clinical trials and are validated and FDA approved to rerun algorithms on previous patients to diagnose disease we didn't see?Eric Topol (08:03):Well, that is a really big important question because basically we're relieving all this stuff on the table that doesn't get diagnosed, can't be predicted because we're not even looking for it. And now whether it's retina, that is a gateway to so many systems of the body, or as you're mentioning various scans like an abdominal CT and many others that like mammography for heart disease risk and all sorts of things that weren't even contemplated that machine eyes can do. So it's really pretty striking and upending cancer diagnosis, being able to understand the risk of any individual for particular types of cancer so that you can catch it at the earliest possible time when it's microscopic before it spreads. This, of course, is a cardinal objective. People don't die of cancer per se. They die of its metastasis, of course, for the most part. So that gets me now to the next phase of ai because what we've been talking for mostly so far has been what has been brewing culminating for the last five years, which is medical images and what, there's so many things we can glean from them that humans can't including expert humans in whatever discipline of medicine.Multimodal AI and Social Determinants of Health(09:19):But the next phase, which you are starting to get at is the multimodal phase where you're not just taking the images, you're taking the medical records, the EHRs, you're getting the genomics, the gut microbiome, the sensors. You mentioned one, an ECGs, a cardiogram sensor, but other sensors like on the wrist, you're getting the environmental things like air pollution, air quality and various things. You're getting the whole ball of wax any given individual. Now, that's kind of where we're headed. Are you doing multimodal ai? Have you already embarked in that new path? Now that we have these large language modelsJohn Halamka (10:02):And we have, and so like anything we do in healthcare innovation, you need a Pareto diagram to say, what do you start with and where do you go? So in 2020, we started with all of the structured data problems, meds, allergies, labs. Then we went to the unstructured data, billions of notes, op reports, H and Ps, and then we moved to telemetry, and then we moved to CT, MRI, PET. Then we move to radiation oncology and looking at all the auto contouring profiles used in linear accelerators and then to omic, and now we're moving to an inferred social determinants of health. And let me explain that for a minute.(10:45):Exposome, as you point out, is really critical. Now, do you know if you live in a Superfund site area, do you know what risks you might have from the PM 2.5 particulates that are blowing through San Diego? Probably you don't. So you're not going to self-report this stuff. And so we have created something called the house Index where we've taken every address in the United States, and based on the latitude and longitude of where you live, we have mapped air, water, land, pollution, access to primary care, crime, education, grocery stores, stores, and therefore we can infer about 40 different things about your expose em just from where you live. And that's a mode. And then as you say, now, starting to gather remote patient monitoring. We have this acute advanced care in the home program where we're taking serious and complex illness, caring for the patient in the home, starting to instrument homes and gather a lot more telemetry. All of that multimodal data is now available to any one of the 76,000 employees of Mayo and our partners for use in algorithm development.Eric Topol (11:58):Yeah, no, that's extraordinary. And I also would say the social determinants of health, which you've really gotten into as its importance. There are so many papers now over the last several years that have emphasized that your zip code is one of the most important things of your health. And it's not even just a zip code. It's your neighborhood within that zip code for the reasons that you've mentioned. And inferring that and imputing that with other sources of data is vital. Now, this multimodal, you've again anticipated one of my questions, the possibility that we can gut hospitals as we know them today. Yes, preserving the ICUs, the emergency departments, the operating rooms, but those other people that occupy the vast majority of beds in the hospital that are not very sick, critically Ill. Do you think we're going to move as you're innovating at Mayo whereby we'll be able to keep those people at home for the most part in the years ahead? I mean, this isn't going to happen overnight, but do you think that's where we're headed?The Hospital-at-HomeJohn Halamka (13:08):So to date, Mayo and its partners have discharged about 23,000 patients from their homes. And as you can guess, we have done clinical trials and deep dive studies on every one of the patient's journeys. And what have we seen across 23,000 patients? Well, so generally, about 30% of patients that present for acute care to an emergency department come in by ambulance are appropriate for care in non-traditional settings. I mean, I think you would agree, somebody with episodic ventricular tachycardia, you're probably not going to put in a home setting, but somebody with congestive heart failure, COPD, pneumonia, I mean, these are things that, as you say, if they're going to get sicker, it will be over hours, not minutes. And therefore you can adjust in these molar than 20,000 patients. What we've seen is the outcomes are the same, the quality is the same safety, the same patient satisfaction. You get net promoter scores in the mid-nineties. You find me a hospital with a net promoter score in the mid nineties. You're eating your own food, slipping your own bed. Oh, your granddaughter's coming at 2:00 AM on a Sunday, whatever. And then ask yourself this other question, nosocomial infections,Eric Topol (14:31):Right?John Halamka (14:31):How many methicillin resistant staph infections do you have in your office? You're like, none, right? So you're infections in fall, so okay, better, stronger, cheaper, faster. And the safety of the quality are that for about 30% of the population should be a standard of care.Eric Topol (14:56):That's really big. So you don't think we have to do randomized trials to prove it?John Halamka (15:01):I mean, we have done enough studies to date, and there are organizations, Kaiser Permanente, Cleveland Clinic, all these folks who are joining us in investigating these areas. And the data is very compelling.Patients Asking Questions to LLMsEric Topol (15:17):Yeah, that's really exciting. And we may be able to jump past having to go through the large trials to prove what you just reviewed. So that's one thing of course that we're looking for in store. Another is the patient doing advanced large language model searches. So as you and everyone knows, we've done Google searches for years about symptoms, and inevitably people come up with hypochondria because they have some horrible disease that they looked up that is not a very good match specific for their condition and their background. But soon already today, we have people going into being creative mode, G P T four and other searches, and they're getting searches about their diagnosis and about what's the best literature and best treatments and expectations. That won't be FDA regulated. We don't have regulation of Google searches. So how do you see the democratization of large language models with patients having conversations with these chatbots?John Halamka (16:32):And of course, you ask a question no one has answered yet, but here are a few threads. So we know the challenge with existent commercial models as they're trained on the public internet. Some are trained on additional literature like PubMed or a mimic dataset, but none are trained on the rich clinical experience of millions and millions of patients. So therefore, they don't have the mastery of the care journey. So question, we are all asking, and again, no one knows. Then you take a GPT, BARD, a MedPaLM and additional pre-training with rich de-identified clinical experience and make it a better model for patients who are going to ask questions. We've got to try and we've got to try within guardrails and guidelines, but we definitely want to explore that. Can you or should you train a foundational model from scratch so that it doesn't have the bias of Reddit and all of the various kinds of chaff you find on the public internet? Could be very expensive, could be very time consuming. Probably society should look at doing it.Eric Topol (17:50):So this is just a review for those who are not up to speed on this, this means setting up a base model, which could be 20 to 30,000 graphic processing units, big expense. We're talking about tens of millions, but to do it right, so it isn't just a specialized fine tuning of a base model for medical purposes, but something that's de novo intended that no one's done yet. Yeah, that's I think a great idea if someone were to go down that path. Now you, early on when we were talking, you mentioned partners, not just other health systems, but one of the important partners you've established that's been out there as Google, which I think set up shop right in Rochester, Minnesota, so it could work closely with you. And obviously they have MedPaLM2, they have BARD, they published a lot in this space. They're obviously competing with Microsoft and others, but seems like it's mainly an arms race between those two and a few others. But how is that relationship going? And you also were very right spot on about the concerns of privacy, federated ai, privacy computing. Can you tell us about Mayo and Google?What is the Collaboration Between Mayo and Google?John Halamka (19:06):Well, absolutely. So Google provides storage, compute, various kinds of tools like their fire engine for moving data between various sources. Google does not have independent access to any of Mayo's data. So this isn't a situation of we have a challenging medical or engineering problem, bring 60 Google engineers to work on it. No, what they mean is they help us create the tooling and the environment so that then those with permission, Mayo employees or Mayo's partners can work through some of these things and build new models, validate models. So Google has been a great enabler on the tool set and building scale. You probably saw that Eric Horvitz gave a recent grand rounds at Stanford where he explained scale makes a difference, and that you start to see these unexpected behaviors, this emerging goodness, when you start dealing with vast amounts of multimodal data, vast amounts of compute. And so working with a cloud provider is going to give you that vast amounts of compute. So again, privacy, absolutely essential, de-identify the data, protect it, control it, but you can't as an institution, get enough computing power locally to develop some of these more.Towards Keyboard Liberation and Machine Chart ReviewEric Topol (20:36):Well, that goes back to the dilemma about building a base model with just the capital costs no less. You can't even get these GPUs scale because their supply and demand mismatch is profound. Well, the other thing, there's two other areas I want to get your impressions about. One of course is the change of interactions with patients. So today, as you well know, having all these years overseeing the informatics, Beth Israel now Mayo, the issue of the keyboard and the interference that it provides, not just as a data clerk burden to clinicians, which is horrible for morale and all the hours even after seeing patients that have to be put into charting through the EHRs and these clunky software systems that we are stuck with, but also the lack of even having face-to-face eye contact with patients in that limited time they have together. Now, there are many of these so-called ambient AI language, natural language processing, using large language models that are of course turning that conversation not just to a remarkable note, but also of course any part of the note, you could go back to the raw conversation. So it has trust embedded as what was really said. And then you have all these downstream functions like prescriptions, follow-up appointments, nudges to the patients about whatever, like their blood pressure or things that were discussed in the visit. You have translation to the patient at their level of education so they can understand the note you have things that we never had before. You have orders for the test or follow up appointment pre-authorization. What about these, John, are these the real deal or are we headed to this in the near term?John Halamka (22:41):So 10 years ago, I said all of these meaningful use criteria, all the keyboarded data entry, structured data and vocabularies. What if you had the doctor and the patient had a conversation and the conversation was the record? That was the legal record. And then AI systems extracted the structured data from the conversation. And there you would have satisfaction by both patient and doctor and a very easy source of truth. Go back to what was said. And of course, 10 years ago everyone said, that'll never happen. That's too far.(23:20):And so I'll give you a case. My mom was diagnosed with a brain abscess about a year ago. She's a cure of the brain abscess. I with ambient listening, had a conversation with my mother and it went something like this. Yes, I started to develop a fever. I said, oh, and you live alone, right? Oh, yes. My husband died 13 years ago. The note comes out, the patient is an 81 year old widow. So we're having a conversation about my father dying and she lives alone. And I didn't use the word widow, she didn't use the word widow. And so what it shows you is these systems can take detailed conversation, turn them into abstract concepts and record them in a way that's summarized and meaningful. Last example I'll give you recently, I did grand rounds at Mayo and I said, here's a challenge for all of us. It's Sunday at three in the morning. Mrs. Smith has just come in. She has a 3000 page chart, 75 hospitalizations and four or visits. Her complaint tonight is, I feel weak,Eric Topol (24:38):Right? That's a classic.John Halamka (24:43):How are you going to approach that? So we have an instance of MedPaLM2 that is containerized. So that I was able to put a prompt in it with some background data without, and it was all de-identified, but it was all very secure. So I put the 3000 pages into this MedPaLM2 container and said, audience, ask any question that you want. Oh, well, what medication should she be taking? What's her follow-up plan? Were there any complications in any of her surgeries? And within seconds, every answer to every question just appears. They say, oh my God, I can now treat the patient. And so this is real. It is absolutely. It's not perfect, but give us a couple of quarters.Eric Topol (25:31):Yeah, quarters not even years. I think you're putting the finger on something that a lot of people are not aware, which is when you have complex patients like what you just described, that woman, and you have so much information to review, no less the corpus of the medical literature, and you have help with diagnosis treatments that you might not otherwise thought of. It also gets me back to a point I was going to make the machine vision during colonoscopy where it does pick up these polyps, but it was shown that at the end of the day in the afternoon for gastroenterologists that are doing colonoscopies all day, their pickup rate drops down. They get tired, their eyes are just not working as well. And here your machines, they don't get tired. So these things are augmenting the performance of physicians, clinicians across the board potentially.(26:28):And yes, there's a concern as you touched on about confabulation or hallucinations, whatever, but this is a work in progress. There will be GPT-X, BARD-15 or whatever else right now, another area that is hot, which is still very in the earliest nascent stage, is the virtual medical coach. Whereby any of us with all our data, every visit we've ever had, plus our data that's in real time accruing or scans or slides or whatever it is, is all being fed in process with the medical literature and helping us to prevent a condition that we would have high risk to develop or manifest or better management of the various things we do have that we've already declared. What about that, John? Are we going to see virtual medical coaches like the kind we see for going to the airport, or you have an appointment such and such about your daily life, or is that something that is way out there in time?John Halamka (27:37):I know you're going to hate this answer. It depends.Eric Topol (27:41):Okay. I don't hate that. I like it actually. Yeah.John Halamka (27:44):So some years ago, one of my graduate students formed a virtual coaching company, and what he found was patients would often start with a virtual coach, but they wouldn't stick with it because the value add wasn't necessarily there. And that is it wasn't then every day there was something new or actionable. And so if it's few and far between, why do you want to go through the effort of engaging in this? So I think our answer there is we need to make sure that the person who uses it is getting something of value for using it. Reduced insurance rates, free club memberships to a gym, whatever, something of value. So it gets some stickiness.Virtual AI CoachingEric Topol (28:33):Yeah. Well, it's still early and right now, as you well know, it's really confined to certain conditions like diabetes or depression or high blood pressure. But it certainly has the chance in the years ahead to become broad for any individual. And that gets back to the patient scenario that you presented where you had all the data of that woman who presented with weakness as the inputs. And just think about that happening in real time, giving feedback to any given individual, always thinking that it's optional. And as you say, maybe it'd be more elective. There were incentives, and if people don't want it, they don't have to use it, but it's something that's out there dangling as a potential. Well, of the things we've discussed, there are many potential ways that AI can be transformative in the future, both for clinicians, for health systems, for patients. Have I missed anything that you're onto?John Halamka (29:40):Just that in predictive AI, we can judge performance against ground truth. Did you have the disease or not? Did you get a recommendation that was followed up on and it was positive? With generative ai measuring quality and accuracy, doing follow up and oversight is much harder. So I think what you're going to see is FDA and the office of the national coordinator and the White House work through generative AI oversight. It's going to start with, as we've seen voluntary oversight from some of the companies themselves. And it will evolve into maybe some use cases that are considered reasonable practices and others that we defer reasonable practices. Hey, you want an agent that will pre-draft your email and then you just edit it, that's fine. And Mayo is live with that in Epic inbox. How about help you write a letter or help you take, as you say, a very complex medical condition, explain it in eighth grade English or a foreign language. Very good at all of that differential diagnosis, not quite ready yet. And so I think we'll start with the administrative use cases, the things that reduce burden. We'll experiment with differential diagnosis. And I don't think we yet have line of sight to say, actually, we're going to have the generative ai do your diagnosis(31:09):Not there yet,Machines Promoting EmpathyEric Topol (31:10):Right? Perhaps we'll never be, particularly for important diagnoses, maybe for routine things that are not a serious matter. One thing that I didn't anticipate, and I want to get your view. When I wrote deep medicine, I was talking about restoring the patient-doctor relationship and the gift of time that could be garnered from having this machine support. But now we're seeing the evidence that the AI can promote empathy. So for example, reviewing a doctor's note and telling the doctor, you didn't show you're very sensitive. You weren't listening, making suggestions for being a more empathic physician or nurse. Did you foresee that too? Because you've been ahead of the curve on all this stuff.John Halamka (32:04):So here's an interesting question. You and I are physician, scientist, writers. How many physician scientist writers are there? Not so many. So what you get are brilliant math or brilliant science, and it is communicated very badly. So I did not anticipate this, but I'm saying the same thing you are, which is you can take a generative AI and take something that is not very digestible and turn it to something highly readable. And whether that's empathy or clarity or whatever, it actually works really well.Eric Topol (32:43):Yeah. Yeah. I mean, I kind of stunned by this because the machines don't know empathy. They can't feel empathy, but they can promote it. And that's really fascinating. So this has been an uplifting discussion. A lot of the things that's happening now give credit to you that you saw coming long before others, and it's a real joy. So we got to keep up with each other. We got to do some more brainstorming on the things that we haven't discussed today. But thanks so much, John, for joining me and for being such a bright light for the work you're doing with Mayo Clinic as a president of its platform. That's no question. Transforming the future of healthcare.John Halamka (33:25):Well, hey, thanks for having me. And I would say both you and I have taken the digital Hippocratic Oath. We will do no digital harm.Eric Topol (33:33):Love it. Get full access to Ground Truths at erictopol.substack.com/subscribe