Ground Truths

Azeem Azhar, an award-winning entrepreneur and innovator in technology, discusses the changing healthcare industry, microbiome manipulation, the potential of AI in promoting empathy among clinicians, GLP1 agonists and their impact on our desire for food, concerns and unknowns in medical treatments, and the need for transparent validation studies and civil discourse in medical AI.

A snippet of our conversation belowTranscript of our conversation 8 January 2023, edited for accuracy, with external linksEric TopolIt’s a pleasure for me to have Liv Boeree as our Ground Truths podcast guest today. I met her at the TED meeting in October dedicated to AI. I think she's one of the most interesting people I’ve met in years and the first time I've ever interviewed a professional poker player who has won world championships and we're going to go through that whole story, so welcome Liv.Liv BoereeThanks for having me, Eric.Eric TopolYou have an amazing background having been at the University of Manchester in physics and astrophysics. Back around in 2005 you landed into the poker world. Maybe you could help us understand how you went from physics to poker.From Physics to PokerLiv BoereeAh, yeah. It's a strange story, I graduated as you said in 2005 and I had student debt and needed to get a job I had plans to continue in academia. I wanted to do a masters and then a PhD to work in astrophysics in some way, but I needed to make some money, so I started applying for TV game shows and it was on one of these game shows that I first learned how to play poker. They were looking for beginners and the loose premise of the show was which personality type is best suited for learning the game and even though I didn't win that particular show we were playing for a winner take all prize of £100,000 which was a life changing amount of money had I won it at the time. It was like a light bulb moment just the game and I’ve always been a very competitive person, but poker in particular really spoke to my soul. I always wanted to play in games where it was often considered a boy’s game and I could be a girl beating the boys at their own game. I hadn't played that much cards in particular, but I just loved any game that was very cutthroat which poker certainly is. From that point onwards I was like you know what I'm going to put physics on hold and see if I can make it in this poker world instead and then never really looked back.Eric TopolWell, you sure made it in that world. I know you retired back in about 2019, but that was after you won all sorts of world and European championships and beat a lot of men. No less. What were some of the things that that made you such a phenomenal player?Liv BoereeThe main thing with poker is well the most important ingredient if you really want to make it as a professional is you have to be extremely competitive. I have not met any top pros who don't have that degree of killer instinct when it comes to the game that doesn't mean it means you're competitive in everything else in life, but you have to have a passion for looking someone in the eye, mentally modeling them, thinking how to outwit them and put them into difficult situations within the game and then take pleasure in that. So, there’s a certain personality type that tends to enjoy that. The other key facet is you have to be comfortable with thinking in terms of probability. The cards are shuffled between every hand so there's this inherent degree of randomness. On the scale of pure roulette which is all luck no skill to a game like chess which has almost no luck (close to 100% skill as you can get) poker lies somewhere in the middle and of course the more you play the bigger the skill edge and the smaller the luck factor. That's why professionals can exist. It's a game of both luck and skill which I think is what makes it so interesting because that's what life is really, right? We're trying to get our business off the ground, we're trying to compete in the dating market. Whatever it is. We're doing our strategy, the role of luck life can throw your curved balls that you can do everything right and still things don't go the way you intended them to or vice versa, but there's also strategies we can employ to improve our chances of success. Those are the sort of skills that poker players particularly this idea of gray scale probabilistic thinking that you really have to hone. I've always wondered whether having a background in science or at least you know studying having ah a scientific degree helped in that regard because of course the scientific method is about understanding variables and minimizing uncertainty as much as possible and understanding what cofounding factors can bias the outcome of your results. Again, that's always going on in a poker player's mind, you'll have concurrent hypotheses. Oh, this guy just made a huge bet into me when that ace came out, is it because he actually has an ace or is it because he's pretending to have an ace and so you've got to weigh all the bits of information up as unbiased as possible in an unbiased way as possible to come to a correct conclusion. Even then you can never be certain, so this idea of understanding biases understanding probabilities I think that’s why a lot of top poker players have backgrounds in scientific degrees a very good friend of mine he had a PhD in in physics. Especially over time poker has become a much more sort of scientific pursuit. When I first allowed to play it was very much a game of street smarts and intuition in part because we didn't have the technological tools to understand really the mechanics of the game as well. You couldn't record all your playing data if you were playing just in a casino unless you were writing down your hands. Otherwise, this information wasn't getting stored anywhere, but then online poker came along which meant that you could store all this data on your laptop and then build tools to analyze that data and so the game became a much more technical scientific pursuit.Eric TopolThat actually gets to kind of the human side of poker. Not the online version —especially since we're going to be mainly talking about AI the term “poker face” the ability to bluff is that a big part of this?Liv BoereeOh, absolutely. You can't be a good poker player if you don't ever bluff because your opponents will start to notice that so that means you're only ever putting your money on the line when you have a good hand so why would they ever pay you off. The point of poker is to maximize the deception to your opponents so you have to use strategies where some of the time you might be having a strong hand and some of the time you might be bluffing where you might have a weak hand. The key is this is getting into the technical sort of game theory side of it, but you want to be doing these bluffs versus what we call value bets as in betting with a good hand with the right to sort of frequency. You need these right ratios between them, so bluffing is a very core part of the game and yes having a poker face obviously helps because you want to be as inscrutable to your opponents as possible. At the same time online poker is an enormously popular game where you can't see your opponent's faces.Eric TopolRight, right.Liv BoereeYet you can still bluff which could actually lead us into this topic of AI because now the best players in the world are actually AIs.Eric TopolWell, it's interesting because it takes out that human component of being able to bluff and it may be good for people who don't have a poker face. They can play online poker and be good at it because they don't have that disguise if you will.Liv BoereeRight.Game Theory and Moloch TrapsEric TopolThat gets me to game theory and a big part of the talk you gave at the TED conference about something that I think a lot of the folks listening aren't familiar with— Moloch traps. Could you enlighten us about that because what the talk which of course we’ll link to is so illuminating and apropos to the AI landscape that we face today?Liv BoereeYeah, I’ll leave it for people to go and watch the TED talk because that's going to be much more succinct than me to explain the backstory of how it came to be called a Moloch trap because Moloch is a sort of biblical figure a demon and it seems strange that you would be applying such a concept to what's basically a collection of game theoretic incentives, but essentially what a Moloch trap is the more formal name for it is a multipolar trap which some of the listeners may be familiar with. Essentially a Moloch trap or a multipolar trap is one of those situations where you have a lot of competing different people all competing for 1 particular thing that say who can collect the most fish out of a lake. The trap occurs when everyone is incentivized to get as much of that thing as possible so to go for a specific objective, but if everyone ends up doing it then the overall environment ends up being worse off than before. What we're seeing with plastic pollution – It’s not like packaging companies want to fill the oceans with plastic. They don't want this outcome. It doesn't make them look good. They're all caught on the trap of needing to maximize profits and external and one of the most efficient ways of doing that is to externalize costs outside of their P&L by using cheap packaging that perhaps ends up in the lakes or the oceans and if everyone ends up doing this but well basically you're a CEO in a decision of I could do the more expensive selfless action, but if I don't do that then I know that my competitors are going to do the selfish thing. I might as well do it anyway because the world's going to end up in roughly the same outcome whether I do it or not because everyone ends up adopting this mindset they end up being trapped in this bad situation. Another way of thinking of it is if you're watching a football at a stadium or a concert and before the show starts everyone's sitting down, but then a few people near the front want to get a better view so they stand up. That now forces the people right behind them to make a decision. I don't really want to block the people behind me but I can't see anymore, so now I have to stand up. The whole thing sort of falls down until everyone is now stuck standing for the rest of the show. No one really actually has a comparative advantage anymore. No one's got a particularly better view than before because it's just the same that now everyone's standing, but overall everyone is net worse because now they have to stand for the whole thing and there's no easy way for everyone to coordinate. A Moloch trap is the result of a competitive landscape where the individual short-term incentives push people to take actions that from a God's eye view from the whole from the whole system's perspective makes everyone worse off than before and because there are so many people it's too hard for everyone to coordinate and really go back to the state before so it creates these kind of arms race dynamics these tragedy of the commons. These are all a result of these Moloch traps which is essentially just another name for bad short-term incentives that hurt the whole overall.Eric TopolNo, that's great. You know someday you should write the book on competition because you have a deep understanding of that. You understand the whole range from healthy, sometimes we call managed competition. The kind that brings out the best in people to unhealthy, I might even call reckless competition, as I mentioned when we were together. Now let's go to as you say arms race nuclear, there's so many examples of this but in the AI world you were polite during your talk because you referred to one of the major CEOs without actually mentioning his name about making another one of the large AI companies titans. Make them dance as part of the competition and I think you came on to something very important which is we're interested in the safety of AI. As we move towards what seems to be inevitable artificial general intelligence, we'll talk more about that there's certainly concerns at least by a significant perhaps plurality of people that this is or can be dangerous. The fact that these this arms race if you will of AI is ongoing. What are your thoughts about that? How seriously bad is this competition?“I hope with our [ChatGPT] innovation they will want to come out and show that they can dance. I want people to know we made them dance”—Satya Nadella, Microsoft CEO, on GoogleThe A.I. Arms RaceLiv BoereeIf it were the case that building powerful AI systems that it was trivially easy to align them with the best of humanity and minimize accidents then we would want more competition because more competition would encourage everyone to go faster and faster and we would want to get to that point as fast as possible. However, if we are in the world where it is not trivially easy to align powerful AI systems with what we want and make sure that they could not do reward hacking or create some kind of unintended consequence but fall into the wrong hands easily you know into the hands of people who want to use it for the various purposes then we wouldn't want as much competition as possible because that would make everything go faster. The thing is when your trajectory is pointing in the wrong direction the last thing you want is more speed, right? I have not yet seen a compelling argument that the current trajectory is sufficiently aligned with what is good for humanity and certainly not for the biosphere that we rely upon. This is not just with AI I mean it's the wider sort of techno capital system in many ways. Obviously, capitalism has been wonderful for us. We are living here speaking across the airwaves in a warm, comfortable environments. We have good food and God bless capitalism for providing us all with that. At the same time there are clearly externalities piling up in our biosphere whether it's through climate change whether it's through pollution and so on and so forth. One particular thing about AI is that if we're going to hack the process of intelligence itself it means intelligence by definition ubiquitous. It can be used to increase the process. It can be but can be used to make more of whatever you want to do. You can do it more efficiently faster more effectively. If you think the system is aligned with exactly what we want then that's a good thing, but I see lots of evidence of the ways it is not sufficiently aligned and I'm very concerned that if we're not thinking in more depth about which goals we should be optimizing for in the first place then we're going to just keep blindly going forward as fast as possible and create a bunch of unintended consequences or even in some cases intended ones with as I said it falling into the wrong hands of people.Eric TopolYou're right on it, I think the issue is how to get the right balance of progress versus guardrails.Liv BoereeYou mentioned this particular CEO that I quoted in the TED talk again I won't mention him by name, but anyone can go Google he basically said I want people to know we made our competitor dance and the reason why that resonated with me so much is because it reminded me of my old self in my early 20’s when I first learned to play poker and as I said you need this to win at poker which is by definition a 0 sum game you need this cutthroat almost bordering on psychopathic type willingness to like go after your opponents and get them by the throat metaphorically speaking to get their money, right? That mindset can be very useful when you're playing a game where the boundaries are clearly defined. Everyone is opting in and there's minimal externalities and harms to the wider world, but if you're using that same mindset to build something as powerful as artificial general intelligence which we don't know whether that's no one's certain whether it's going to be trivially easy whether it's impossible whether it will be controllable, whether it be completely uncontrollable, whether we're making a new species, whether it's just another tool or technology. No one really knows, but what I do know is that that is not the mindset or the impetus we want of the leaders building such incredibly powerful tools. Tools that couldn't be used to make them more powerful than any human and ever in history, tools that they may even lose control of themselves, we don't know That's really what alarms me the most is that first of all, we might have leaders who have that mindset in the first place but again even if they were all very wise and positive some mindset they weren't out there trying to just compete against each other and it's like pardon my French but like dick swinging contest even if they were perfectly enlightened they're still trapped in this difficult game theoretic dilemma this Moloch trap. I want to let my team build this safely as a priority, but I know that the other guys might not do it as safely, so if I go too slowly, they're going to get there ahead of me and deploy their really powerful systems first, so I have to go faster myself. Again, what suffers if everyone's trying to go as fast as possible the slow boring stuff like safety checks like evaluation testing etc. This is the real the fundamental nature of the problem that we need to be having more honest conversations about it's twofold. It's the mindset of the people building it. Now again some of them I know some of them personally, they're amazing people. Some of these CEOs I deeply respect and I think they understand the nature of the problem and they're really trying to do their best to not fall into this Moloch mindset, but there are others who truly are just wanting to I don't know solve some childhood trauma thing that they have through. I don't want to psychoanalyze them too much but whatever's going on there plus you have the game theoretic dilemma itself and we need to be tackling both of these because we're building something as powerful. Whether again it's AGI or not even narrow AI systems. LLMs are getting increasingly generalizable multimodal, they're starting to encroach into your area of expertise into biology I was reading about which I can't remember which chatbot it was but there's a really cool paper you guys could link to on archive talking about whether LLMs could be used to democratize access to use of technology like DNA synthesis. Is that something we want no safeguards on because that's sort of what we're careening towards and there are people actively pushing to be like no, that you can't deny anyone access to information. Google right now if you search if you Google how do I build a bomb. There's it's something like they just put it on front page. That information they don't give you the step-by-step recipe and yes, okay, you could go and get your chemistry degree and get some books and figure out how to build a bomb, but the point is there's a high barrier to entry and as these LLMs become more generalizable and more and more accessible we have this problem where the barrier to entry for anyone who is really murderous or omnicide or a terrorist mindset these are going to be falling into the hands of more and more of these people it’s going to be easier and easier for them to actually get hold of this information and there is no clear answer of what to do with this because how do we strike a balance between allowing free flow of information so that we're not stifling innovation which it also would be very terrible or even worse creating some kind of centrally  controlled top-down tyrannical control of the internet saying who can read what that's an awful outcome, but then in and the other direction we can't have it widely available to but people like ISIS or whoever how to build a pathogen that makes COVID look like the common cold. How do we navigate this terrain where we don't end up in tyranny or self-terminating chaos. I don't know but that those are the problems. That's all we have to figure out.Effective AltruismEric TopolThe idea that you conceptualize what's going on in AI as a Moloch trap I think is exceedingly important but now you also cited that there were a few companies that deserved at least credit with their words such as OpenAI where they're putting 20% of their resources towards alignment and Anthropic as well as DeepMind that's done a lot of great work with AlphaFold2 and life science, but as you said these are just words we haven't seen that actually translated into action. As we go forward one of the terms tossed around a lot that also was surrounding Sam Altman's temporary dismissal and brought back to OpenAI is effective altruism What is EA?Liv BoereeThere's two ways of thinking about EA. There's the body of ideas, the principles which to summarize them as quickly as I can and as best as I understand them would be there are many different problems on earth there are only finite resources in terms of intellectual capital and actual capital in order to be spent on fixing these problems and so because of that we need to triage and figure out where is the most effective place to spend our time and money in order to solve these problems. How do we rank these problems in terms of scale and electiveness and so on and then how do we deploy our resources as efficiently and as effectively as possible in order to achieve these big problems. So those are the sort of principles and then. Out of those principles over time sprang up a community of people who adhere to those principles and in part have been very aligned with that I started a fundraising organization alongside some other poker players back in 2014 following these principles and encouraging poker players basically to donate to a range of different charities. Most of which were to do with because it if you want to save a life on average the most cost-effective way to do that averages out to people in sub-Saharan Africa dying from extreme poverty related illnesses particularly malaria turns out that providing bed nets on average will save a life for about $5000 from malaria there's vitamin A supplementation etc. That was my involvement I'm going off track, but that was my involvement in EA, but basically out of that sprang a movement and as that movement evolved then it became there were sort of different categories because it's very hard to concretely go well that's definitely problem number one because you have some which are well right now we know that there are this many people dying per day needlessly from this particular tropical disease or you could zoom out and go okay but over the next thirty years these are the kind of risks that civilization is facing so actually if we give that a 10 % probability then that could be 10 % of this many people so actually this is the biggest issue or you could go I care more about I don't just care about human lives I care about animal lives in which case then you. Then math would lead you to conclude that factory farming is actually the biggest issue particularly the amount of needless suffering that is going on factory farms like there's small rules changes that could be made in the way that these animals are treated during slaughter or raised pigs in gestation crates. Small changes there could have a huge positive impact on billions upon billions of animals' lives per year so out of these ideas sprung sort of different subcategories of EA of people focusing on different areas depending on what their personal calculations may led them to and of the category of sort of risks to humanity AI if you follow the if appreciate the game theoretic dilemmas that are going on and see just how fast things are going and how much safety is fallen by the wayside there's strong arguments that AI becomes a very important topic. Effective altrurists became from what I can see very concerned about AI long before almost the rest of the world did and so they became I guess kind of synonymous with the idea of AI safety measures and then I don't really understand well I mean there's reasons why I guess that that seems like the way the Sam Altman thing came up was because two members of the board have been associated with AI safety and effective altruism and they were 2 of the 3 that seems like they tried to you know, vote him out. Then this whole hooha drama came up about it and I wish I knew more I would love to know their reasons why they felt like Sam had to go. What it seems like again I'm purely speculating here but what I've heard through the grapevine was that it was more to do with him lying and misrepresenting them as opposed to a safety concern, but I don't know so that's the I guess Sam Altman EA drama.The AGI ThreatEric TopolIn many ways it's emblematic of what we've been talking about because you know there were a couple of board members that were there was a lot of angst regarding pushing hard on AGI. Whether or not there are other things of course that's a different story, but this is the tension we live in now that is we have on one hand some leaders like Yann LeCun, Andrew Ng who are not afraid who say you know still humans are going to be calling the shots as this gets more and more refined to whatever you want to call AGI, but more comprehensive abilities for machines to do things. The other the real concerns like Jeff Hinton and so many others have voiced which is we may not be able to control this, so we'll see how this plays out over time.Liv BoereeLook I hope that Andrew Ng and Yann LeCun turn out to be right. I deeply hope so, but I have yet to see them make compelling arguments because really the precautionary principle should apply here, right? When we're when we're playing such high stakes when we're gambling so high and there's a lot of people who don't have any skin in the game whose lives are on the line even if it's with a very small probability then you need to have real air type proof that your systems will do exactly what you want them to and even with ChatGPT-4 when it came out you know obviously there wasn't a threat to humanity in any explicit way, but that went through six months of testing before they released it. Six months and they got lots of different people. They put a lot of effort into testing it to make sure that it reliably did what they wanted it to when users used it. Within three days of it being available on the internet there were all kinds of unintended consequences coming up. It made the front page of The New York Times. Even with six months of testing I believe you know OpenAI really worked hard to make that be as bounded as possible and they thought they'd I'm sure they were expecting some things to slip through, but it was trivial once you got thousands of users on it figuring out ways to jail break it.Liv BoereeThere hasn't been that's surely a data point to show that you know even with lots of testing this is not a trivially easy problem the people building a machine will always be able to control it and as systems get more and more powerful and more and more emerging properties come out of them as they increase in complexity that's what emergent seems to do. If anything is going to become harder to predict everything that they could do not easier and it's I don't know I as I say I would love for Yann and Andrew to be correct, but even I think even both of them when pushed for example on the topic of what about controlling access to LLMs that could be used for pathogen synthesis in some way or as a sort of put as a tool to help you figure out which DNA synthesis companies have the least stringent checks on their on their products and we'll just send you anything because that some really do have very low stringency there. They didn't have a good answer to that they couldn't answer it and they'll just sort of go back to yes, but you can't constrain information. It's still yeah, you have to give it all for free. It's like you can't be an absolutist here like there are tradeoffs. Yes, and we have to be very careful as a so civilization not to swing too much into censorship or to swing too much into just like letting all guardrails off. We have to navigate this, but it is not comforting to me as a semi layperson to see leaders who are building these technologies dismiss the concerns of alignment and unintended consequences as like trivially easy problems when they clearly aren't that's not filling me with confidence. They're hubris— I don't want a leader who's showing hubris and so that's end of my rant.Eric TopolIt's really healthy to kind of vet the ideas here and that's what's really unique about you Liv is that you have this poker probabilistic thinking you know competition is fierce as it can be and how we are in such exciting times, but also in many ways daunting with respect to you know where we're headed where this could lead to and I think it's great. I also want to make a plug for your Win-Win that's perfect name for a podcast that you do and continue to be very interested in your ideas as we go forward because you have such a unique perspective.Liv BoereeThank you so much, I really appreciate you plugging it. I remain optimistic there's a lot of well-intended people. Incredibly brilliant people working within the AI industry who do appreciate the nature of the problem. The question is I wish it was as simple as oh, just let the market decide just let profit maximization guide everything and that will always result in the best outcome I wish it was that simple that would make life much easier, but that's not the case externalities a real, misalignment of goals is real. We need people to reflect on just be honest, over the fact that move fast, and break things is not the solution to every problem and especially when the possible things you are breaking are the is the very biosphere or playing field that we all rely on and live on. Yeah, it's going to be interesting times.Eric TopolWell, we didn't solve it, but we sure heard a very refreshing insightful perspective. Liv, thanks for what you're doing to get us informed and to learn from other examples outside of the space of AI and your background and look forward to further discussions in the future.Liv BoereeThank you so much. Really appreciate you having me on. Get full access to Ground Truths at erictopol.substack.com/subscribe

The science to advance our understanding of the aging process—and to potentially slow it down—has made important strides. One of the leading scientists responsible for this work is Professor Tony Wyss-Coray, whose work has particularly focused on brain aging but has implications for all organs. I believe his December 2023 Nature paper on blood proteins that can track aging for 11 of our organs is one of the most important aging reports yet.Here is the audio and transcript of our conversation, recorded 20 December 2023, with a few relevant external links.This is the last Ground Truths post for 2023 and I hope you’ll find it informative. I look forward to sharing many more exciting, cutting-edge biomedical advances with you in 2024!00:10.38Eric TopolHello this is Eric Topol and for this edition of Ground Truths. I'm so delighted to have with me Professor Tony Wyss-Coray of Stanford, a Distinguished Professor at Stanford and who directs the Knight Initiative for Brain Resilience. So welcome Tony.00:30.19Tony Wyss-CorayThank you, thank you for having me, Eric.00:32.84Eric TopolWell, I've been following your career and your work for decades I have to say and what you just published a couple weeks ago in Nature. The cover paper about internal organ clocks. It blew me away. I mean it's a built on a foundation of extraordinary work. I thought we could start with that because to me that's really a breakthrough in that when we think of aging and how to gauge a person aging with things like the Horvath clock of methylation markers or telomeres or —not at all specific to any part of the body, just overall, l but you published an extraordinary work about plasma proteins for 11 organs that predicted the outcomes things like heart failure and Alzheimer's so maybe you could tell us about this.  Seems to be a big deal to me.01:28.41Tony Wyss-CorayThank you so much I'm honored. Really, you know I think if you work on this stuff, especially for several years it feels sort of obvious to do it? But I think you know it is in a way. It is. Pretty simple. So what we argued is that the thousands of proteins that you know are present in our blood. They must originate from somewhere now a lot of proteins are you know, produced by cells throughout the body. But some proteins are very specifically produced. For example, only in the brain or only in the liver or only in the heart because they have specialized functions and we have you know being taking advantage of that in clinical medicine where you measure. Often you know one of these proteins to sort of diagnose pathology in a tissue, but we took this It's just a level further and said, well, let's just find out of thousands of proteins that we can measure assign them to specific organs and tissues. And then see whether they change with age and many of them turn out to change. We found you know about 1500 proteins or so in the study that we did although that number can grow dramatically if we you know keep.03:01.11Tony Wyss-CorayImproving our technologies or techniques to measure them and many of them come from the brain or from other tissues and because they change with age. They tell us something about the aging of that organ. And as others have shown in the field including Steve Horvath is that that prediction of the age if it doesn't really match exactly your actual age contains information about the state the physiological state or the risk to develop. Organ-specific disease.03:37.75Eric TopolRight. And you found that about 1 in 5 people had evidence of accelerated aging of 1 organ which of course is really starting to nail down ability to detect aging you know to localize it and um. What strikes me Tony is that now because we're seeing at the cusp of advancing in the science of aging a field that you have done so much to propel forward and one of the issues has been well, how are we going to prove it. We can't wait for 20 years to show that. Whatever intervention led to promotion of healthy aging. But when you have a marker like this of organ specificity, it seems like the chances of being able to show that intervention makes a difference is enhanced would you say so?04:29.28Tony Wyss-CorayYeah, absolutely I think that's one of the most exciting aspects of this that we can now start looking at interventions whether they are you know a specific intervention that tries to target the aging process, or you know just that. Let's say a cholesterol lowering drug or blood pressure lowering drug does that have a beneficial effect on the heart. For example, on the kidney or you can also start thinking of lifestyle interventions where they actually have an effect right? If you started exercising you collect your blood before and then a year after you have an exercise regimen does that actually change the age that we can measure with these different clocks.05:22.55Eric TopolRight? Well I mean it's really a striking advance and by a marker of aging so that gets me to your other work. You've done well over 10 years which is that you could identify that given young blood. First of course in mice and then later verified in people could improve cognitive function in older whether it's experimental models or in people. So what are your thoughts about that is that if that's something you've been ruminating on for many years and I’m sure there are places around the world that are trying to do this sort of thing. What do you think of that potential?06:11.40Tony Wyss-CorayYeah, so there really this recent observation or study really came out of you know that finding that young blood can change the age of different organs and you know we. We were not the first to show this. We showed it for the brain but Tom Rando who studied muscle stem cell aging showed this you know a few years earlier in the muscle and we worked with Tom to explore this for the brain, but it shows sort of that this you know the composition of the blood. It is really not just reflecting the age of organs and tissues. But it actually also affects them. It directs them in a way and so you can speculate that you know if you had an organ that shows accelerated aging. Because some of the factors end up in the blood. They might actually induce aging in other tissues and so promote the aging process and people in the field have also shown that this is true for specific cells. We call them senescence cells. So these are a specific type of cell that seem to somehow stop dividing and assume the state that releases inflammatory factors these cells too. They seem to almost infect the neighborhood where they live in with an age promoting sort of.07:41.95Tony Wyss-CorayThe secretome , as we call it, so they release factors that seem to promote aging locally but potentially across the organism and interfering in that could potentially have rejuvenating effects and so that brings us back to this observation that.08:01.23Tony Wyss-CorayYoung blood could potentially rejuvenate organs We know old blood can accelerate it at least in mice. So could we neutralize the age promoting factors in people and could we deliver sort of the rejuvenating factors. Now what's been frustrating for me is that it has been incredibly challenging to identify the key factors.08:33.30Tony Wyss-CorayI think we became to realize as a field that there is not 1 factor. There's not 1 magic factor that will keep us young or keep our organs young but rather different cells and different organs in our body seem to respond in different ways actually to this young blood. Can show this with molecular tools. We can show that every cell actually responds. So if you take a mouse an old mouse and you give it young blood every cell in that mouse shows a transcription of the response to the young blood.09:10.80Tony Wyss-CoraySome of them may regenerate mitochondria and others activate other pathways. We see that stem cells respond particularly well the stem cells of the Immune system hematopoietic stem cells um while other cells show less of a response. And that to me suggests that they respond to different factors in the young blood and that you know they have very specific um receptors Probably that recognize some of these beneficial factors and then respond in a specific way. So that’s what we need to.09:33.16Eric TopolRight.09:48.63Tony Wyss-CorayFigure out I think as a field to translate this really to the clinic is what are the key factors and will it be possible to make a cocktail that sort of mimics Nature's you know elixir10:06.13Tony Wyss-CorayI Said this before it's almost like the fountain of youth is within us, but it just dries out as we get older and if we could figure out what are the key factors that that make up this fountain. We could potentially you know either, as a treatment, deliver it again or reactivate that found and so that the body produces these factors again.10:34.73Eric TopolWell, you know that's something that years ago I was very skeptical about and because of your work and others in the field. I've come a long way thinking that we're on the cusp of really identifying ways to truly promote healthy aging. And so this is a really you know extraordinary time in our lives I wonder you of course mentioned 2 critical paths that have been identified the senescent cells—removing them— or the infusion of young plasma. Would you say it's too simplistic to reduce this to decreasing inflammation or is that really the theme here, or is it much more involved than that.11:28.48Tony Wyss-CorayI think inflammation has a big part in that but you know inflammation is such a broad term and such an ill-defined term that um yeah I can say yes to your question.11:44.45Tony Wyss-CorayAnd I'm probably not going to be wrong. Um, but if we really want to know which molecular pathways in the inflammatory cascade are key to this detrimental process that seems to accelerate aging. Um, I think we have to work a bit harder and really so define what we're saying you can't just have thousands of proteins or genes that have something to do with immune and inflammatory process. It's called inflammation.12:21.25Tony Wyss-CorayThen? yes, everything is inflammation. But I think we have to be more precise. Otherwise, you can't really target it. Having said that you know if we use sort of the conventional tools that biologists use these pathway analyses if we give young plasma. To an aged organism then the top pathway or one of the top pathways in almost every cell is inflammation, suggesting that we reduce the inflammatory process. But again, it's in a very broad sense and I want to know more? what? what. What we're finding? In fact, you know 1 of our first observations when Saul Villeda was in my lab and the first parabiosis study to look at factors that might promote brain aging. Yeah, he identified beta-two-microglobulin and eotaxin is a chemokine that is involved in a lot of you know, sort of inflammatory responses and has actually recently more recently again been implicated by Michelle Monje here at Stanford. To be a mediator of you know the chemobrain as people call it at least in animal models and we showed that it's part of the age plasma that causes sort of, an acute impairment of cognitive function in mice.13:46.90Tony Wyss-CoraySo that would be an example of a bad factor and that is part of an inflammatory cascade but we want to know what exactly is it. Um, we tried a small molecule that targets the receptor One of the main receptors for this chemokine. But unfortunately that compound had some side effects on the liver and we've never got to really test. The question is this you know potentially Important. It's one of the challenges you know for drug development.14:20.82Tony Wyss-CorayYou often don't get to test your questions because the drug has side effects that don't allow you to do that.14:26.14Eric TopolWell, speaking of drugs out there this past week there was a very provocative paper from Daniel Drucker University of Toronto on the GLP-1 effects on brain inflammation and interestingly with. You may have seen it but with mice that were either knocked out of GLP-1 for their blood cells or their brain. It was clear that inflammation reduction with these drugs and they tested several different GLP-1s, all worked through the brain. Which is really fascinating and I wonder of course these drugs are now you know they craze for anti-obesity. But do you see something like that this this peptide agonist as a potential way to achieve some of the effects that you've been. Working on for a long time.15:25.40Tony Wyss-CorayYeah I think this is extremely fascinating. Um I mean these drugs. Um, we don't understand them exactly what they're doing as you know for many drugs.15:31.24Eric TopolRight? right? right.15:37.13Tony Wyss-CorayBut it's really amazing the effects that you see and you know I'm very hopeful. There's a large phase 3 trial in Alzheimer's disease ongoing. The phase 2 looked very positive very promising so you know it. It is really possible that.15:49.65Eric TopolUm, yeah.15:56.49Tony Wyss-CorayUm, that there that there are key pathways that are responsible for you know cognitive decline and a cognitive impairment and inflammation is ah is a key aspect of that again inflammation in a broad term. We need to define it but it could be that it goes through. You know, um through these glib receptors and um and that ah might be ah, some regulator of a broader process but you know we see for example with aging just with normal aging you get um activation of.16:35.96Tony Wyss-CorayInflammatory pathways in the brain vasculature and young plasma reduces these changes acutely and maybe this is you know all part just dampening that inflammation gives you some additional brain power, if you will, for lack of a better word. That much of you know at least the early stages of cognitive impairment that lead to Alzheimer's disease.17:12.10Tony Wyss-CorayRelatively transient and are more like a fog like we say you know the chemofog the chemobrain or brain fog but that you know with Covid that you also commented very prominently that. That suggests that it's not a structural damage early on but that that it might be some soluble factors that would go a long way if you could just suppress them.17:35.83Eric TopolRight? right? Well, It's really fascinating to see and I'm glad you mentioned the Phase 3 trial in Alzheimer's for this one class because I think that's expected in 2025 to read out and that'll be really important. I Wanted to ask you because now there's many shots on goal to change the natural arc of aging at all these companies like Altos and Unity and Calico and I mean there's so many of them I can't even keep track. Um, they're all taking different strategies. I Have to think because they need to have their own intellectual property. What do you see as the alluring ways that we're going to be able to modulate this process.18:25.65Tony Wyss-CorayThat's a very tough question. I think it's hard to predict I would say you know like always in in biology. First of all, as you know what we discussed earlier. It could be that. Ah, drug that tries to test the pathway like you know one that Unity tried has side effects and you know you can't actually test your hypothesis. But I think one of the key sort of aspects of the aging process is really that it's both global across the organism but it's also very localized and so it's possible that targeting the aging process will first show benefits. In individual tissues if we target you know the aging process in 1 particular tissue that might show the first benefits. But then again it could be that if there is sort of a key inflammatory driver that to some extent responsible for overall aging of the organism and you manage to target that and slow it or block it. You may have an organism-wide effect. But I think we have to be we have to be realistic that.19:51.88Eric TopolUm, yeah.19:56.99Tony Wyss-CorayYou know this is going to be an incremental process I think.20:00.92Eric TopolSo is there anything that you've seen that has grabbed you as having tremendous potential that is new or is it really you know the things that I've already been percolating that that we know about.20:17.41Tony Wyss-CorayYeah I mean just to the GLP-1 study I've been actually ah a bit involved in that. Um I find this really fascinating. Um, yeah.20:23.98Eric TopolUm, yeah, yeah, well that I spoke.20:29.81Tony Wyss-CorayI Mean not in that study that got published but in sort of more on the cognitive side.20:33.78Eric TopolWhere I right? I Thought that was especially welcome news because the drugs we have now for Alzheimer's seem to have you know some pretty serious side effects and somewhat low efficacy relative to the to the risk rssessment. So, this would be a drug that we know now as people have taken for years that I do want to get back to you with you on the durability. So if you give young blood to an old person who has let's say mild Cognitive impairment. Will you see a durable impact or is it just a very short lived one.21:13.76Tony Wyss-CorayI think some of the effects will be durable and I'm saying that because of an experiment that James White and Vadim Gladyshev did they use this parabiosis model where you suture a young and an old mouse together.21:32.10Tony Wyss-CorayLeft these mice together for two months I mean or three months and then they separated them and let them live and looked at how long does an old mouse live that was paired with a young mouse for a few months. Compared to an old mouse that was paired with another old mouse and they saw that there is clear extension of lifespan if the mouse was exposed to young blood. Now this is in the context of you know, 2 major surgeries first suturing them together and then taking them apart. But I always note that when I present this experiment but I also say at the same time that this is the problem that a lot of older people have right when they have a surgery they don't recover from it as well. And it's often the beginning of cognitive decline if you ask families. You know when did it start? Oh they had heart surgery or they fell and had you know had a hip surgery or something like that or a major infection. That is often the trigger where it's almost like you know the organism is hanging in there and it's still functioning and then there's an injury and it collapses. Um and so you know what's remarkable with the rejuvenating intervention with.23:02.11Tony Wyss-CorayWith parabiosis is that it seems to overcome this to a very significant event and they also showed you know with many other tools including with the Horvath clock that tissues are actually getting younger through this process.23:20.51Tony Wyss-CorayWe have also found that you know stem cells are rejuvenated for a long period of time if you treat with young plasma infusions in mice and so I'm hopeful that some of the effects are going to be long-lasting. But. You know, practically you would probably still treat people on a regular basis like we do with all drugs. But maybe you would do an infusion every 3 months or every six months and you know we're still trying with um.23:52.20Eric TopolPray.23:57.00Tony Wyss-CorayA company that I so that that I started Alkahest to you know, convince people to do a Phase 3clinical trial and see how far we can push this.24:09.38Eric TopolWell, it'd be really interesting to see you get that done then going back to the senescent cells which is another leading prospect. It seems to be more difficult to get these cells out of the body. We know they're bad actors but it isn't like we can you know. Ah, very selectively remove them. But what are your thoughts about that approach.24:35.76Tony Wyss-CorayI mean I'm always really puzzled and amazed at the effects that people show with you know, senescence cell removal in in animal models.24:46.20Eric TopolRight.24:49.57Tony Wyss-CorayThere is something really almost magical there that you remove these few cells and you know the body is doing much better. Um, So I think you know we should. We should keep trying very hard to translate this to humans. But it's possible that again there are they're very likely different types of senescence cells and different tissues I mean in the brain you know there are no rapidly dividing cells. So. It's not the classic. You know arrest of cell cycle.25:24.11Tony Wyss-CorayBut it's probably more like an astrocyte type of cell that might mimic a senescent state.  But I think it will be. It will be. You know very much organ specific. And may require very specific interactions or drug targets.25:44.83Eric TopolAh, right? right? Well then gets us back to kind of where we started before you're what I consider a landmark paper. Um, it would be difficult. To be able to go to a regulatory body like the FDA and say we show that this is affecting the aging process and we show in you know 3 organs 5 organs whatever the 11 organs you could track we are reversing the aging process. I mean you have that now as an extraordinary finding. Do you think that will help accelerate the field by having not having to have a whole-body aging story with an epigenetic clock but rather you know much more pinpointing. Organs that can be helped that they can be promoting healthy aging. It seems to me this is where not only advancing the theories of how to do it but the proof that you have done it. It seems like this is what. You know why I consider such an extraordinary finding.26:59.90Tony Wyss-CorayI totally agree with you but I'm a bit biased I think you know this is what we need I mean this was always a criticism to me and you know we're very good friends with Steve Horvath andMorgan Levine who you know came up with these remarkable aging clocks. But my my question was always how can you get information about the whole body aging. By looking at changes in blood cells or cheek cells. Um, that cannot contain information about how your pancreas ages or your heart ages at the high resolution. It will correlate. Admittedly, but it will not give you tissue-specific information most likely. So you know going more directly at molecules that are derived from cells across the organism is of course going to be much more informative. Um, we've just started to do this. You know it's a concept. Um, we are super excited about you know, looking now at large datasets like the UK biobank. We just get access. Through a collaboration to 50,000 individuals where we have 1500 protein measurements with a different proteomic platform and it seems most of the findings replicate.28:47.45Tony Wyss-CorayYou know, very strong risk for people who have older brains to develop the men in the future. Um, and you know we still see these extreme organ ages that I find very puzzling.29:00.89Eric TopolYeah, it's really striking and the fact that you could replicate the best biomarker for the brain.—Plasma pTau-181— through these proteins is exceptional. How much did machine learning AI help you? And deciphering this large data set of proteins was it really critical or was it just a small part.29:26.23Tony Wyss-CorayAh, oh it's certainly I mean this is I think you know the terminology are not so clear and I have to admit you know I'm not a computer scientist by any stretch. But I think this is classic machine learning using statistical elements of learning as you know. We use linear modeling. Um, but I think it will become more sophisticated. Um, and I think ai will help us to bring this. To a much higher level by but by basically learning from the relationship between proteins directly and then compare that in healthy people versus control similar to what Christina Theodoris recently did for gene expression. Ah, the single cell level. Um I think we will see that and we're trying this and I'm sure others are trying this too at the protein level but the current the current study uses really more traditional machine learning models. Um that you know are sophisticated but it's not.30:42.33Tony Wyss-CorayYou know I'm not sure we call this artificial intelligence.30:44.85Eric TopolSure. Well I think as you say it can build on that and you know putting in more models to more data sets and where the future goes. You'll get even more precision output as you know know, Tony.30:51.58Tony Wyss-CorayUm, yeah. Absolutely.31:02.44Eric TopolThis This has been a real joy. I have to say congratulations to you and your team for such exceptional work. This has been a multi-decade run, you know one layer of after another of building on the science of aging particularly the brain aging I've learned so much from you and your team.31:07.28Tony Wyss-CorayThank you.31:21.81Eric TopolI have to say the paper you just published you and your group got me excited I mean I really thought of all the things I’ve seen on aging this was the one that really opens it up for you know all the other possible ways to claim you're making a difference. You've got a metric that's emerging and so kudos to you and I know this is got to be of course that you probably just say oh, it's just 1 more thing we've been doing but I am so duly impressed.31:52.30Tony Wyss-CorayThank you so much. Thank you for the nice word means a lot.31:58.94Eric TopolWell keep up the great stuff because we're all, we're all depending on you so that we can have a better arc of our healthy aging process and we'll keep in touch. If you can just stay on it!32:10.30Tony Wyss-CorayThank you! Thanks so much.Thank you for listening, reading, subscribing to and sharing Ground Truths!Happy new year,Eric Get full access to Ground Truths at erictopol.substack.com/subscribe

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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