Holden Thorp, Editor-in-Chief of the Science family of journals, discusses overseeing six journals, the revolution in science reporting towards medicalization, navigating politics in academia, AI in science publishing, the broad definition of a scientist, and challenges faced by academia with citizen science and misinformation.

Discussions on the convergence of AI and digital biology, exponential growth in AI technology, implications for drug discovery, aging interventions, and the innovative platform approach to revolutionize drug discovery by merging engineering, data, and machine learning.

“A few years ago, I might have chuckled at the naiveté of this question, but now it's not so crazy to think that we will be able to take some sort of medicine to extend our healthy lifespans in the foreseeable future.”—Coleen MurphyTranscript with external linksEric Topol (00:06):Hello, this is Eric Topol from Ground Truths, and I'm just so delighted to have with me Professor Coleen Murphy, who has written this exceptional book, How We Age: The Science of Longevity. It is a phenomenal book and I'm very eager to discuss it with you, Coleen.Coleen Murphy (00:25):Thanks for having me on.Eric Topol (00:27):Oh yeah. Well, just so everyone who doesn't know Professor Murphy, she's at Princeton. She's the Richard Fisher Preceptor in Integrative Genomics, the Lewis-Sigler Institute for Integrative Genomics at Princeton, and director of the Paul Glenn Laboratories for Aging Research. Well, obviously you've been in this field for decades now, even though you're still very young. The classic paper that I can go back to would be in Nature 2003 with the DAF-16 and doubling the lifespan of C. elegans or better known as a roundworm. Would that be the first major entry you had?Coleen Murphy (01:17):Yeah, that was my postdoctoral work with Cynthia Kenyon.Eric Topol (01:20):Right, and you haven't stopped since you've been on a tear and you’ve put together a book which has a hundred pages of references in a small font. I don't know what the total number is, but it must be a thousand or something.Coleen Murphy (01:35):Actually, it's just under a thousand. That's right.Eric Topol (01:37):That's a good guess.Coleen Murphy (01:38):Good guess. Yeah.Eric Topol (01:39):So, because I too have a great interest in this area, I found just the resource that you've put together as extraordinary in terms of the science and all the work you've put together. What I was hoping to do today is to kind of take us through some of the real exciting pathways because there's a sentence in your book, which I thought was really kind of nailed it, and it actually is aligned with my sense. Obviously don't have the expertise by any means that you do here but it says, “A few years ago, I might have chuckled at the naivety of this question, but now it's not so crazy to think that we will be able to take some sort of medicine to extend our healthy lifespans in the foreseeable future.” That's a pretty strong statement for a person who's deep into the science. First I thought we'd explore healthy aging health span versus lifespan. Can you differentiate that as to your expectations?Coleen Murphy (02:54):So, I think most people would agree that they don't want to live necessary super long. What they really want to do is live a healthy life as long as they can. I think that a lot of people also have this fear that when we talk about extending lifespan, that we're ignoring that part. And I do want to assure everyone that the people in the researchers in the aging field are very much aware of this issue and have, especially in the past decade, I think put a real emphasis on this idea of quality of life and health span. What's reassuring is actually that many of the mechanisms that extend lifespan in all these model organisms also extend health span as well and so I don't think we're going to, they're not diametrically opposed, like we'll get to a healthier quality of life, I think in these efforts to extend lifespan as well.Eric Topol (03:50):Yeah, I think that's important that you're bringing that up, which is there's this overlap, like a Venn diagram where things that do help with longevity should help with health span, and we don't necessarily have to follow as you call them the immoralists, as far as living to 190 or whatever year. Now, one of the pathways that's been of course a big one for years and studied in multiple species has been caloric restriction. I wonder if you could talk to that and obviously there's now mimetics that could simulate that so you wouldn't have to go through some major dietary starvation, if you will. What are your thoughts on that pathway?Coleen Murphy (04:41):Yeah, actually I'm really glad you brought up mimetics because often the conversation starts and ends with you should eat less. I think that is a really hard thing for a lot of people to do. So just for the background, so dietary restriction or caloric restriction, the idea is that you would have to take in up to 30% less than your normal intake in order to start seeing results. When we've done this with laboratory animals of all kinds, this works from yeast all the way up through mice, actually primates, in fact, it does extend lifespan and in most metrics of health span the quality of life, it does improve that as well. On the other hand, I think psychologically it's really tough to not eat enough and I think that's a part that we kind of blindly ignore when we talk about this pathway.Coleen Murphy (05:30):And of course, if we gave any of those animals the choice of whether they want to start eating more, they would. So, it's like that's not the experiment we ever hear about. And so, the idea for studying this pathway isn't just to say, okay, this works and now we know how it works, but as you pointed out, mimetics, so can we target the molecules in the pathway so that we can help people achieve the benefits of caloric restriction without necessarily having to do the kind of awful part of restriction? I think that's really cool, and especially it might be very good for people who are undergoing certain, have certain diseases or have certain impairments that it might make it difficult ever to do dietary restrictions, so I think that's a really great thing that the field is kind of getting towards now.Eric Topol (06:15):And I think in fact, just today, it's every day there's something published now. Just today there was a University of Southern California study, a randomized study report comparing plant-based fasting-mimicking diet versus controlled diet, and showed that many metabolic features were improved quite substantially and projected that if you stayed on that diet, you'd gain two and a half years of healthy aging or that you would have, that's a bit of an extrapolation, but quite a bit of benefit. Now, what candidates would simulate caloric restriction? I mean, what kind of molecules would help us do that? And by the way, in the book you mentioned that the price to pay is that the brain slows down with caloric restrictions.Coleen Murphy (07:10):There's at least one study that shows that.Coleen Murphy (07:13):Yeah, so it's good to keep in mind. One of the big things that is being looked at as rapamycin, looking at that TOR pathway. So that's being explored as one of these really good mimetics. And of course, you have things that are analogs of that, so rapalogs, and so people are trying to develop drugs that mimic that, do the same kind of thing without probably some of the side effects that you might see with rapamycin. Metformin is another one, although it's interesting when you talk to people about metformin who work on it, it's argued about what is exactly the target of metformin. There's thought maybe also acts in the TOR pathway could affect complex one of mitochondria. Some of the things we know that they work, and we don't necessarily know how they work. And then of course there's new drugs all the time where people are trying to develop to other target, other molecules. So, we'll see, but I think that the idea of mimetics is actually really good, and that part of the field is moving forward pretty quickly. This diet that you did just mention, it is really encouraging that they don't have to take a drug if you don't want to. If you eat the right kind of diet, it could be very beneficial.Eric Topol (08:20):Yeah, no, it was interesting. I was looking at the methods in that USC paper and they sent them a box of stuff that they would eat for three cycles, multiple weeks per cycle. It was a very interesting report, we'll link to that. Before we leave the caloric restriction and these mTOR pathway, you noted in the book that there some ongoing trials like PEARL, I looked that up and they finished the trial, but they haven't reported it and it's not that large. And then there's the FAME trial with metformin. I guess we'll get a readout on these trials in the not-too-distant future. Right?Coleen Murphy (08:57):Yeah, that's the hope that especially with the Metformin trial, which I think is going to be really large the FAME trial, that just to give the listeners a little background, one of the efforts in the field is not just to show that something works, but also to convince the FDA that aging could be a pharmaceutical, a disease that we might want to have interventions for. And to do that, we need to figure out the right way to do it. We can't do 30-year studies of safety and things to make sure that something's good, but maybe there are reasonable biomarkers that would tell us whether people are going to live a long time. And so, if we can use some of those things or targeting age-related diseases where we can get a faster readout as well. Those are reasonable things that companies could do that would help us to really confirm or maybe rule out some of these pharmaceuticals as effective interventions. I think that would be really great for consumers to know, is this thing really going to do good or not? And we just don't have that right now in the field. We have a lot of people saying something will work and it might and the studies in the lab, but when we get to humans, we really need more clinical studies to really tell us that things are going to be effective.Eric Topol (10:12):Right, I'm going to get to that in a bit too because I think you're bringing up a critical topic since there's an explosion of biopharma companies in this space, billions of dollars that have been put up for in capital and the question is what's going to be the ground rules to get these potential candidate drugs to final commercial approval. But before I leave, caloric restriction and insulin signaling and the homolog and the human to what your discovery of DAF-16, FOXO and all this, I just want you to comment, it wasn't necessarily developed in the book, but as you know, the GLP-1 drugs have become just the biggest drug class in medical history, and they do have some effects here that are very interesting. They are being tested as in Alzheimer's disease. Do you see that this is a candidate too that might promote healthy aging?Coleen Murphy (11:12):Yeah, I'm so glad you brought that up because my book, I finished writing it right before all this stuff came out, and it's looking really very compelling. People are on these drugs, they lose a ton of weight, but their blood biomarkers really become very good and on top of just the changes in weight and those kinds of effects. Let me just say, I think the biggest thing, the biggest risk actually for aging people right now are cardiovascular problems, cardiovascular disease, and these drugs, no doubt, it's going to basically make a huge dent in that. I'm absolutely sure of that. What I also find really interesting with those drugs is that the users report that they have fewer cravings for other things. So, this is not being looked at to treat alcoholism and drug addiction, other things, so it really opens up a whole new world of things that are bad for us that maybe we could avoid this with these peptides. It's almost staggering. I really think this going to be a huge, and as far as an aging drug, if you reduce your weight, you improve all your cardiovascular function, you don't feel like drinking all the time, all these things might be really great and I do think that people will live longer.Eric Topol (12:32):Yeah, no, it does have that look and you just have to wonder if as these will go on to oral drugs with triple receptors and very potent, maybe even avoiding peptides in the future too, that this could wind up being something that's exceedingly common to take for reasons far removed from the initial indication of type two diabetes and more recently of course, obesity. Now the next topic I wanted to get into with you were senolytics, these agents that basically are thought to reverse aging or slow aging. And again, since everything's coming out in a daily basis, there was a trial in diabetes macular edema where giving senolytic after people had failed their usual VEGF treatment was highly successful. So, we're starting to see, at least in the eye results. I wonder if you could describe how you conceive this field of senolytics?Coleen Murphy (13:41):Actually, I think they've made great progress in the past couple of years because there were some initial failures, like some of the things for osteoarthritis that went through I think phase two, but I think that one of the great things about the longevity biotech field is that they're starting to identify not just longevity, these age-related disorders that they could actually use. And so, it's kind of doubly beneficial. It tells us that the drugs actually do something and so maybe it'll be used for something else in the future and you get through, you can test safety, but also helping people actually have a very real problem that's acute that they really need to take care of. And so that's really exciting. Then in addition to the example you just mentioned, I was at a conference last summer where it was being explored whether some of these senolytics could be helpful for middle aged survivors of childhood cancers who do show various health effects from having gone through chemotherapies at a young age. So that's really exciting. Could you help people who are not aging, but they actually are showing having problems that we kind of associate with aging. And senolytics were at least the first thing I'd heard about that are actually being used for that, so there may be other approaches that help as well, but I think that's really great.Eric Topol (15:05):Well, and just to be clear the senolytics, I guess could be categorized at least one function might be to help clear dead cells. These senescent cells are bad actors and either they're taken out or they're somehow neutralized in their impact of secreting evil humors, if you will. Are there other forms of senolytics besides that way of dealing with these senescent cells?Coleen Murphy (15:33):I know that some people are exploring senomorphs, so things that make those cells just arrest but I do want to mention, of course, we lost a great Judith Campisi recently, and she was the one who discovered and described the senescent associated secretory phenotype, and she did amazing work in that field really opening that up. So, this idea that bad cells aren't just bad because they don't function, but they're actually toxic to other cells.Coleen Murphy (16:04):That's important for listeners to know. Yeah, so I don't know. I think that one of the things I'm excited about in the aging field is that it doesn't seem like there's one magic bullet. A lot of researchers will spend their time working on that one thing so if you only talk to that one person, you might get that impression, but there's a whole host of things that for bad or good, that things go wrong when we age, but those all end up being maybe targets that could help us live longer or at least in a healthier way. And so, we've already talked about a couple of them, but readers will see as we learn more, there might be more ways to help cells survive or to help us replace ourselves, for example.Eric Topol (16:45):I mean, I think what you're bringing up here is central because there's all these different, as I can see it, shots on goal that of course could be even used as combinations, no less senolytic interventions so we're getting closer as we started this conversation to fulfilling what you, I think is in store in the years ahead, which is extraordinary. Along with the senolytics, I wonder if you could just talk a little bit about these autophagy enhancers as a class of agents, maybe first explaining autophagy and then is this a realistic goal that we should be taking autophagy enhancers, or is this something that's too generalized that might have onward mTOR effects?Coleen Murphy (17:39):Well, it's interesting. Autophagy, so just for the listeners, autophagy literally means self-eating. So this is a pathway whereby proteins basically get degraded within the cell and those parts get recycled. And the idea is that if you have a cell or protein that's damaged in some way, or it can be renewed if you induce autophagy. I think I could be wrong here, but my sense is that the cancer field is really excited about autophagy enhancers. And so, I think that's probably where we'll see the biggest breakthroughs but along the way, of course we'll know because we'll know if they're safe and if there's other off-target effects. I think that that's largely being driven by the cancer field and the longevity field is kind of a little bit behind that, so we'll learn from them. It seems like a really exciting approach as well.Eric Topol (18:34):Yeah, it does. And then as you know, the idea of giving young blood, young plasma, which there already are places that do this, that it can help people who are cognitively impaired and have basically immediate effects, and sometimes at least with some durability. It's very anecdotal, but this idea, we don't know what's in the young blood or young plasma to some extent. How do you process that?Coleen Murphy (19:10):Okay. Well, so what we do know, and this is really work that a lot of people like Saul Villeda and Tony Wyss-Coray have done where they really have, they've taken that blood or plasma and then found the parts in the plasma that actually do specific jobs. And so, we actually are starting to learn a lot about that and that's exciting because of course, we don't really want to give people young blood. What we really would like to do is find out is there a particular factor in the blood? And there seems to be many that could be beneficial. And so, we really are getting close. We as a field, and specifically like the research I just mentioned and that's exciting because you can imagine, for example, if there's one factor that's in blood, that's in young blood, that's very helpful, manufacturing, a lot of that particular thing.Coleen Murphy (20:01):The other exciting thing, again, this is Saul Villeda’s lab that found that exercise mice. So even if they're the same age mice, if one of them is exercised, it makes factors that actually from the liver of the mouse upon exercise, that then gets secreted and then affect, improve cognitive function as well. So it seems like even within the blood, there's multiple different ways to get blood factors that are beneficial, whether they're from young blood or from exercise blood. And so, there's a lot of things we don't yet know, but I do think that field is moving very fast and they're identifying a lot of things. In fact, so I'm the director of Simons Collaboration Plasticity in the Aging Brain, and on that website we're developing basically a page that can tell you what are the factors and what has it been shown to be associated with, because we're very interested in slowing normal cognitive aging and blood factors seem to be one of the really powerful ways that might be available to us very soon to be able to improve that.Eric Topol (21:03):Yeah, no, I'm glad you mentioned that, Coleen. I think the point that you made regarding exercise, I certainly was struck by that because in the book, because we've known about this association with exercise and cognition, and this I think is certainly one potential link. An area that is also fascinating is epigenetics, so a colleague of mine here in the Mesa, Juan Carlos Belmonte, who was at Salk and left to go to Altos, one of these many companies that are trying to change the world in health span and lifespan. Anyway, he had published back several years ago.Coleen Murphy (21:53):Yeah, 2016.Eric Topol (21:54):Yeah, CRISPR basically modulation of the epigenome through editing and showed a number of through specific pathways, a number of pretty remarkable effects. I wonder if you could comment about epigenetics, and then I also want to get into this fascinating topic of transgenerational inheritance, which may be tied of course to that. So, what about this pathway? Is there something to it?Coleen Murphy (22:29):Well, absolutely. I just think we need to learn a lot more about it. So just for the listener, so epigenetics, we think about genetics that's basically based on DNA and chromosomes. And so, when we think about epigenetics, that could be either, we could be talking about modulation of the histone marks on the chromosomes that allow the genes to be expressed or be silenced. And then on the DNA itself, there are methylation marks. And so, people have used, of course, Steve developed a, sorry, I'm sorry. Steve Horvath developed a very nice, he was first to develop a DNA methylation clock. So this idea that you could, and that was really interesting because he based it on, he used this machine learning method to narrow down to the 353 marks that were actually predictive or correlated with age, but we don't understand how it biologically what that manifests in. I think that's not well understood. At the chromatin level, there's a lot of work on the specific histone marks that may change, for example, how genes are transcribed and so understanding that better will maybe help us understand what those changes. There's things called epigenetic drift, so genes stop being carefully regulated with age, and then how can we make that maintain better with age? It's one of the goals of the field in addition to basically understanding what's going on at the epigenetic level.Eric Topol (24:01):So now of course, could we alter that? Oh, it is fascinating as you say, that you could have the Horvath clock to so accurately predict a person's biological age. And by the way, just a few days ago, there was a review by all these clock aging folks in nature medicine about the lack of standards. There's so many clocks to basically determine biological age versus chronological age. Before we get into the transgenerational inheritance, what is your sense? Obviously, these are getting marketed now, and this field is got ahead of its skis, if you will, but what about these biologic age markers?Coleen Murphy (25:02):Yeah, I'm glad to hear that. I haven't seen that review. I should look it up. It's good to know that the players in the field are addressing those points. So just for the listeners, so these DNA methylation clocks so when Steve Horvath developed the first one, it was based on the controls from a very large number of cancer controls for other reasons, so he used a huge amount of information. It really depended on the, he was trying to develop a clock that was independent of which tissue, but it turned out there's more and more clocks that are tissue specific and really organism specific, species specific. It really depends on what you're looking at to make these, and whether you're looking at chronological age or trying to predict biological age. I think it's a little frustrating because what you'd really like to know as a consumer, if you send off for one of these clock kits, is it right?Coleen Murphy (25:57):What's the margin of error? If I took it every week, would I get the same number? And so, I think my sense is that people take it until they get a low number then, but you'd really like to know if they work, because if you want to take it, do a control and they start, get your clock number and then start taking some intervention and ask whether it works, right? Yeah. So, I think because the players in the field recognize these issues, they're going to straighten it out, but I think one part that drives a little bit of the problem is that we don't understand what that DNA methylation mark change translates into biologically. If we understood that better, I think we'd have a better feeling about it. Anne Brunet and Tony Wyss-Coray maybe a year and a half ago, they had a nice paper where two years ago where they looked at, they use a different type of clock, a transcriptional clock, and that worked really well. So they were looking at transcriptional clock in the subventricular zone, and they were able to actually see changes not just with age, but also when there was an intervention. I can't remember if they look at dietary restriction and then maybe an exercise in the mice. And so that's important for us to know how well those clocks work.Coleen Murphy (27:13):I think it'll get there. It'll get there.Eric Topol (27:15):You don't want to pay a few hundred dollars and then be told that you're 10 years older biologically than your chronologic age, especially if it's wrong. Right?Coleen Murphy (27:25):Yes. It'll get there. I think it may not be quite there yet.Eric Topol (27:30):And by the way, while we're on that, the organ clocks paper, in fact, just a recent weeks, I did interview Tony Wyss-Coray from Stanford, and we talked about what I consider really a seminal paper because using plasma proteins, they're able to basically clock each organ. And that seems like a promising approach, which could also help prove the case that you're changing something favorably with one of these various intervention classes or categories. Do you think that's true?Coleen Murphy (28:05):That feels more real directly looking at the proteins then.Eric Topol (28:08):Yeah, exactly. I thought that was really exciting work, and I'm actually going to visit with Tony in a few weeks to discuss it further. So excited about it.Coleen Murphy (28:18):That's great. He's doing great work, so it'll be a fascinating conversation.Eric Topol (28:21):Yeah, well this is also fascinating. Now, transgenerational inheritance is a very controversial topic in humans, which it is not so much in every other species. Can you explain why that is?Coleen Murphy (28:38):Well, there's a lot of, I would say emotional baggage attached here, right? Because that's what people are talking about, like transgenerational trauma. There's no doubt that traumatic experiences in childhood actually do seem to change the genome and change have very real biological effects. And that's been shown. So that's within the first generation. It's also no doubt that in other organisms, like in plants like DNA methylation, that's exactly how they regulate things, and that's multiple generations. So that's kind of the norm. And so, the question for humans is whether something like this, like a traumatic experience or starvation or thing, has an effect, not just on the person who's experiencing it, but also on their progeny, even on their grand progeny. And so, it's tough, right? Because the data that are out there are from pretty terrible experiences like the Dutch hunger winter. And so, there's a limited set of data, and some of those data look good, and some of them look weaker. Yeah, I think that we still need to figure out what's going on there, and if it's real, it'd be interesting to know. Are there ways, for example, with these epigenetic modulators, are there ways that you could help people be healthier by erasing some of those marks of trauma, generational trauma?Eric Topol (30:03):Yeah. So, I mean, the theory as you're getting to would be you could change the epigenome, whether it's through chromatin, acetylation, methylation, somehow through these experiences and it would be going through down through multiple generations. The reason I know it's controversial is when I reviewed Sid Mukherjee's book, the Gene, he had put in that it was real in humans, and the attack dogs came out all over the place. Now, we've covered a lot of these pathways. One that we haven't yet touched on is the gut microbiome, and the idea here, of course, it could be somewhat linked to the caloric restriction story, but it seems to be independent of that as well. That is there, our immunity is very much influenced by our gut microbiome. There's the gut brain axis and all sorts of interactions going on there, but what about the idea of using probiotics and particular bacterial species as a introducing the people as an idea in the future to promote health span?Coleen Murphy (31:18):Yeah, it's a great idea. So, I just want to back up and say the microbiome, the reason it's so fraught is because for a long time, people had confused correlation and causation. So, they would see that a person who has X disease has a difference in the microbiome from people who don't have that disease. And so, the question was always, do they have that disease because of a difference in the microbiome or the disease influence in the microbiome? And of course, even things that's eating different food. For example, if a child with autism doesn't want to eat certain range of food, it's going to have an effect on the microbiome. That does not mean the microbiome cause their autism. And so that's something where, and the same thing with Alzheimer's disease patients. I think that's often the source of some of this confusion. I think people wish that they could cure a lot of diseases by taking a probiotic.Coleen Murphy (32:09):On the other hand, now there's actually some really compelling data. Dario Valenzano's lab did a really nice experiment in killifish, which is my second favorite aging model research organism. So killifish, turquoise killifish, only live a few months. And so, you can do aging studies really quickly and what Dario's group did was they took the microbiome at middle aged fish, they wiped out their microbiome with antibiotics, and they added back either young or same age, and they saw a really nice extension of lifespan with the young microbiome. So that suggests, in that case where everything else is the same, it really does have a nice effect. John Cryan’s group in Ireland did something similar with mice, and they showed that there was a beneficial effect on cognitive function in older mice. So those are two examples of studies where it really does seem like there is an effect, so it could be beneficial. And then there's of course things like microbiome transfer for people who are in the hospital who have had other things, because your microbiome also helps you prevent other diseases. Those being there, if you wipe out all of your microbiome, you can actually get infected with other things. It's actually a protective barrier. There's a lot of benefits, I think in order to, we don't know a ton about how to control it. We know there are these, it's gross, but fecal microbiome transplantation.Eric Topol (33:42):FMT. Yeah, yeah.Coleen Murphy (33:44):Exactly. And so, I think that is kind of the extreme, but it can be done. I think in appropriate cases it could be a very good strategy.Eric Topol (33:53):It's interesting. There was a study about resilience of the immune system, which showed that women have a significant advantage in that they have just the right balance of not having a hyper inflammatory reaction to whether it's a pathogen or other stimulus. And they also have, of course, an immunocompetent system to respond, so unlike men overall, that although the problem of course with more prone to autoimmunity because of having two x chromosomes and exist or whatever other factors. But also, there's a balance that there's an advantage, in the immune system as a target for health span and lifespan, a lot of things that we've talked about have some interaction with the immune system. Is there anything direct that we can do to promote a healthier immune system and avoid immunosenescence and inflammaging or immuno aging or whatever you want to call it?Coleen Murphy (35:04):Sure, I will admit that immunology is a field that I want to learn more about, but I do not know enough about it to give a really great answer. I think it's one of the things I kind of shied away from when I wrote the book that if I were to rewrite it, I would add a whole new section on it. I think that's a really booming field, this interaction between immunology and aging. Obviously, there's immune aging, but what does that really mean?Coleen Murphy (35:28):I feel like I can't give you a really intelligent answer about that. Even though I'd like to, and I don't know how much of it's because there's just sort of this general idea that the immune system stops functioning well, but I do feel like the immune system is actually so mysterious. I have a peanut allergy, for example. We don't even really, I mean, we can prime ourselves against that now. We can give kids little bits of peanuts, but all the things that I feel like immunology is the one that's probably taking off the most, and we'll probably in a decade know way more about it than we do now, but I can't give you a very smart answer right now.Eric Topol (36:09):Yeah, no, I do think it's really provocative and the fact that if you have these exhausting T cells that are basically your backup system of your immune system, if they're not working, that's not good. And maybe they can be revved up without being problematic. We'll see.Coleen Murphy (36:27):And I guess the real question is do we need to do something independent or is that folded into everything else? If you were giving someone a drug that seemed very good systemically or some of these blood factors, would you have to do something special just for the immune system or is that something that would also be effective? I feel like that would be good to know.Eric Topol (36:44):Now the other area that I want to bring up, which is a little more futuristic is genome editing. So recently when I spoke to David Liu, he mentioned, well, actually it was Jennifer Doudna who first put it out there, but we discussed the idea of changing the people like me who are APOE4 carriers to APOE2, which is associated with longer life and all these other good things. Why don't we just edit ourselves to do that? Is that a prospect that you think ever could be actualized?Coleen Murphy (37:20):Well, I was just at a talk by Britt Adamson just moments ago, and that field is moving really fast, right? All the work that David Liu has done, and it's really exciting, this idea that you can now cure sickle cell anemia.Coleen Murphy (37:35):Fascinating. And I think Jennifer Doudna rightly proposed early on that what we should really be hitting first are like blood. Blood's really good because it's not hitting the germline. It's really something where we can help people at that stage. I was thinking about that while Britt was talking, what are the things we'd really want to address with CRISPR? I'm not sure how high up in the list aging related factors would be compared to a lot of childhood diseases, things that are really debilitating, but certainly is true since when we're looking at APOE4. I think that's the one exception because that is so strongly correlated with healthy lifespan and Alzheimer's and things, so we really want to do something about that. The question is how would we do that? That's not a blood factor. I think we'd have to think hard about that, but it is on the list of looming on the horizon.Eric Topol (38:35):I wouldn't be surprised if someday, and David, of course thought it's realistic, but it's not, obviously in the short term. Well, this has been enthralling to go through all these possibilities. I guess when you put it all together, there's just so many ways that we might be able to, and one of the things that you also pointed out in your book, which something that should not be forgotten, is the fact that all these things could even worsen the inequities that we face today. That is you have any one of these click, if not multiple, it isn't like they're going to be available to all. And the problem we have now, especially in this country without universal health and access issues, could be markedly exacerbated as we're seeing with the GLP-1 drugs too, by the way.Coleen Murphy (39:27):Absolutely.Eric Topol (39:28):So, I just want to give you a chance to reinforce what you wrote in the book, because I think this is where a lot of times science leads and doesn't realize the practical implications of who would benefit.Coleen Murphy (39:42):Yeah, I think actually for aging research often, even when I first started doing this work back in 2000, the first thing people would ask me if they're below a certain age was, don't you think that's terrible? Make the rich people just live the longest? And they're not wrong about that. I think what it can, we should raise awareness about the fact that even these things that we consider simple, like doing caloric restriction or getting exercise, even those things are not that straightforward if you're working two jobs or if you don't have access to excellent foods in your neighborhood, right? Fruits and vegetables. If we really want to not just extend longevity but raise life expectancy, then we should be doing a lot more that's for improving the quality of life of many people. And so there is that idea. On the other hand, I do want to point out that as we discover more and more of these things, like metformin is off patent, it's like it's really old. And so, it's more of these things get discovered and more broadly used. I do think that that may be a case where we could end up having more people might have access to things more easily. So that's my hope.Coleen Murphy (40:57):I don't want to discourage anyone from developing a longevity dry. I think eventually that could help a lot of people if it's not too absurdly expensive.Eric Topol (41:04):Yeah, no, I certainly agree. And one last footnote is that we did a study called The Wellderly here, about 1,400 people over age 85 who'd never been sick, so our goal here wasn't lifespan. It was to understand if there was genomics, which we did whole genome sequencing of this group. We didn't find much like the study that you cited in the book by the Calico group. And so just to give hope that people, if they don't have what they think are family genetics of short life or short health span, that may not be as much to that as a lot of people think. Any final thoughts about that point? Because it's one that's out there and data goes in different directions.Coleen Murphy (41:55):Yeah. The Calico study you mentioned, I think that's the one where they found that your health or lifespan mostly went with almost like your in-laws, which actually points again to your socioeconomic group probably you marry people, most people marry people are in a similar socioeconomic group. That's probably what that mostly had to do with. I do think if I'm going to say one thing because a lot of these drugs are on the horizon, they're not yet available, or there's nothing I can hang onto for an FDA approved drug to extend that. I do think the one thing that I would encourage people to do even more than the dietary restriction stuff, it is exercise because that's just generally beneficial in so many different ways. And so, if we can get people doing a little more exercise, I think that would be the one thing that probably could help a lot of people.Eric Topol (42:40):Well, I'm glad we are winding up with that because I think the data from lifestyle, which is exercise as you're pointing out, as well as nutrition and sleep.Coleen Murphy (42:54):All the boring things we already thought, right.Eric Topol (42:55):That we know about, but we don't necessarily put in our daily lives. There's a lot there. There's no question that studies, I think, really have reinforced that even recent one. Well, what a pleasure to talk to you about this and do this tour of the various exciting prospects. I hope I haven't missed anything. I know we can't go over all the pathways, and obviously there've been some bust in the past, which we don't need to review like the famous Resveratrol Sirtuin story, which you addressed in the book. I do want to encourage people that this book is extraordinary. Your work that you put into it had to be consumptive for I don't know how many years of work.Coleen Murphy (43:37):There was many years of work. My editor, we sat down to lunch right after it finished. She was like, so what are you going to work on for your next book?Eric Topol (43:50):Well, it's a scholarly approach to a very important field. If you can influence the aging process, you influence every part of our body function. The impact here is profound, and the contribution that you've made in your science as well as in your writing here is just so terrific. So thank you, Coleen. Thanks so much for joining us today.Coleen Murphy (44:17):Thank you so much. It's been a pleasure.Thanks for listening and/or reading this edition of Ground Truths, aimed at bringing you cutting-edge biomedical advances via analyses and podcasts.All content is free. Voluntary paid subscriptions go to support Scripps Research and have funded our summer intern program. 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Transcript with audio and relevant external links, recorded on 6 Feb 2024Eric Topol (00:05):Hello, this is Eric Topol with Ground Truths, and I have a remarkable guest with me today, Professor Michelle Monje, who is from Stanford, a physician-scientist there and is really a leader in neuro-oncology, the big field of cancer neuroscience, neuroinflammation, and she has just been rocking it recently with major papers on these fields, no less her work that's been on a particular cancer, brain cancer in kids that we'll talk about. I just want to give you a bit of background about Michelle. She is a National Academy of Medicine member, no less actually a National Academy of Medicine awardee with the French Academy for the Richard Lounsbery Award, which is incredibly prestigious. She received a Genius grant from the MacArthur Foundation and is a Howard Hughes Medical Institute (HHMI) scholar, so she is just an amazing person who I'm meeting for the first time. Michelle, welcome.Michelle Monje (01:16):Thank you. So nice to join you.Long Covid and the BrainEric Topol (01:18):Well, I just am blown away by the work that you and your colleagues have been doing and it transcends many different areas that are of utmost importance. Maybe we can start with Long Covid because that's obviously such a big area. Not only have you done work on that, but you published an amazing review with Akiko Iwasaki, a friend of mine, that really went through all the features of Long Covid. Can you summarize your thoughts about that?Michelle Monje (01:49):Yeah, and specifically we focused on the neurobiology of Long Covid focusing on the really common syndrome of cognitive impairment so-called brain fog after Covid even after relatively mild Covid. There has been this, I think really important and exciting, really explosion of work in the last few years internationally trying to understand this in ways that I am hopeful will be beneficial to many other diseases of cognition that occur in the context of other kinds of infections and other kinds of immune challenges. But what is emerging from our work and from others is that inflammation, even if it doesn't directly initially involve the nervous system, can very profoundly affect the nervous system and the mechanisms by which that can happen are diverse. One common mechanism appears to be immune challenge induced reactivity of an innate immune cell in the nervous system called microglia. These microglia, they populate the nervous system very early in embryonic development.(02:58):And their job is to protect the nervous system from infection, but also to respond to other kinds of toxic and infectious and immune challenges. They also play in healthy conditions, really important roles in neurodevelopment and in neuroplasticity and so they're multifaceted cells and this is some population of those cells, particularly in the white matter in the axon tracks that are exquisitely sensitive it seems to various kinds of immune challenges. So even if there's not a direct nervous system insult, they can react and when they react, they stop doing their normal helpful jobs and can dysregulate really important interactions between other kinds of cells in the brain like neurons and support cells for those neurons like oligodendrocytes and astrocytes. One common emerging principle is that microglial reactivity triggered by even relatively mild Covid occurring in the respiratory system, not directly infecting the brain or other kinds of immune challenges can trigger this reactivity of microglia and consequently dysregulate the normal interactions between cells and the brain.(04:13):So important for well-tuned and optimal nervous system function. The end product of that is dysfunction and cognition and kind of a brain fog impairment, attention, memory, ability to multitask, impaired speed of information processing, but there are other ways that Covid can influence the nervous system. Of course there can be direct infection. We don't think that that happens in every case. It may not happen even commonly, but it certainly can happen. There is a clear dysregulation of the vasculature, the immune response, and the reaction to the spike protein of Covid in particular can have very important effects on the vessels in the nervous system and that can trigger a cascade of effects that can cause nervous system dysregulation and may feed directly into that reactivity of the microglia. There also can be reactivation of other infections previous, for example, herpes virus infections. EBV for example, can be reactivated and trigger a new immune challenge in the context of the immune dysregulation that Covid can induce.(05:21):There also can be autoimmunity. There are many, we're learning all the different ways Covid can affect the nervous system, but autoimmunity, there can be mimicry of some of the antigens that Covid presents and unfortunate autoimmunity against nervous system targets. Then finally in severe Covid where there is cardiopulmonary compromise, where there is hypoxia and multi-organ damage, there can be multifaceted effects on the nervous system in severe disease. So many different ways, and probably that is not a comprehensive list. It is certainly not a mutually exclusive list. Many of these interactions can happen at the same time in the same individual and in different combinations but we're beginning to wrap our arms around all the different ways that Covid can influence the nervous system and cause this fairly consistent syndrome of impaired attention, memory, multitasking, and executive functions.Homology with Chemo BrainEric Topol (06:23):Yeah, well there's a lot there that you just summarized and particularly you highlighted the type of glia, the microglia that appear to be potentially central at least a part of the story. You also made analogy to what you've seen with chemotherapy, chemo brain. Maybe you could elaborate on that.Michelle Monje (06:42):Yeah, absolutely. So I've been studying the cognitive impairment that can happen after cancer therapies including chemotherapy, but also radiation and immunotherapy. Each time we develop a new model and dig in to understand what's going on and how these cancer therapies influence the nervous system, microglia emerge as sort of the unifying principle, microglial reactivity, and the consequences of that reactivity on other cell types within the nervous system. And so, understanding that microglia and their reactive state to toxic or immune challenges was central to chemotherapy induced cognitive impairment, at least in preclinical models in the laboratory and confirm by human tissue studies. I worried at the very beginning of the pandemic that we might begin to see something that looks a lot like chemotherapy induced cognitive impairment, this syndrome that is characterized by impaired attention, memory, executive function, speed of information processing and multitasking. When just a few months into the pandemic, people began to flood neurologists’ office complaining of exactly this syndrome. I felt that we needed to study it and so that was the beginning of what has become a really wonderful collaboration with Akiko Iwasaki. I reached out to her, kind of cold called her in the midst of the deep Covid shutdown and in 2020 and said, hey, I have this idea, would you like to work with me? She's as you know, just a thought leader in Covid biology and she's been an incredibly wonderful and valuable collaborator along the way in this.Eric Topol (08:19):Well, the two of you pairing up is kind of, wow, that's a powerful combination, no question. Now, I guess the other thing I wanted to get at is there've been many other studies that have been looking at Long Covid, how it affects the brain. The one that's frequently cited of course is the UK Biobank where they had CT or MRI scans before in people fortunately, and then once they had Covid or didn't get Covid and it had a lot of worrisome findings including atrophy and then there are others that in terms of this niche of where immune cells can be in the meninges, in the bone marrow or the skull of the brain. Could you comment on both those issues because they've been kind of coming back to haunt us in terms of the more serious potential effects of Covid on the brain?Michelle Monje (09:20):Yeah, absolutely and I will say that I think all of the studies are actually quite parsimonious. They all really kind of point towards the same biology, examining it at different levels. And so that UK Biobank study was so powerful because in what other context would someone have MRI scans across the population and cognitive testing prior to the Covid pandemic and then have paired same individual tests after a range of severity of Covid infection so it was just an incredibly important data set with control individuals in the same cohort of people. This longitudinal study has continued to inform us in such important ways and that study found that there were multiple findings. One is that there appears to be a small but significant atrophy in the neocortex. Two that there are also abnormalities in major white matter tracts, and three, that there is particular pathology within the olfactory system.(10:30):And we know that Covid induces as a very common early symptom, this loss of smell. Then together with those structural findings on MRI scans that individuals even with relatively mild acute disease, exhibited long-term deficits in cognitive function. That fits with some beautiful epidemiological studies that have been done across many thousands of individuals in multiple different geographic populations. Underscoring this consistent finding that Covid can induce lasting cognitive changes and as we begin to understand that biology, it fits with those structural changes that are observed. We do know that the olfactory system is particularly affected and so it makes sense that the olfactory system, which show those structural changes, the neocortical and white matter changes evident on MRI fit with what we found microscopically at the cellular and molecular level that highlighted a loss of myelinating oligodendrocytes, a loss of myelinated axons, a deficit in hippocampal new neuron production. All of those findings fit together with the structural changes that the UK Biobank study highlighted. So clearly this is a disease that has lasting impacts, and the challenge is to understand those better so that we can develop effective interventions for the many, many millions of people who are still struggling with decreases in their cognitive function long after Covid exposure affecting the world population.The Brain’s Immune SystemEric Topol (12:17):Yeah, that's a great summary of how the Biobank data UK aligned with the work that you've done and I guess the other question just to round this out is for years we didn't think the brain had an immune response system, right? Then there's been a wakeup call about that, and maybe you could summarize what we know there.Michelle Monje (12:41):Absolutely. Yes, the brain is not, we used to call the nervous system an immuno privilege site, and it is not hidden from the immune system. It has its own and distinct immune system properties, but it's very clear from work by Jony Kipnis and others that there are in fact lymphatics in the nervous system. These are in the meninges. It's also become increasingly clear that there is a unique bone marrow niche in the skull from which many of the lymphocytes and other kinds of immune cells that survey and surveil the brain and spinal cord, that's where they come from. That's where they develop and that's where they return and the lymphatic drainage of the nervous system goes to distinct places like the posterior cervical lymph nodes. We are now understanding the sort of trafficking in and out of the nervous system of cells, and certainly understanding how that changes in the context of Covid, how those cells may be particularly responsive to the immune challenge initiated in the respiratory system is something that is an area of deep importance and active exploration. In fact, some of my ongoing collaborations and ongoing lab work focuses on exactly this question, how does the trafficking from the brain borders into the nervous system change after Covid? And how does potentially cellular surveillance of immune cells contribute of the nervous system contribute to the persistent microglial reactivity that we observe?Eric Topol (14:22):And do you have any hunch on what might be a successful worthwhile therapy to a candidate to test prospectively for this?Michelle Monje (14:30):I think it's too early to nominate candidates, but I think that the biology, the molecular and cellular biology is underscoring a role for particular cytokines and chemokines that are initiated by the immune response in the lung. And clear cellular targets, the goal I think the central goal being to normalize the neurovasculature and normalize microglial reactivity and so the question in this disease context and in others becomes, how can we kind of molecularly coach these reactive cells to go back to doing their normal jobs to being homeostatic? That's the challenge, but it's a surmountable challenge. It's one that I think that the scientific community can figure out, and it will be relevant not only to Covid, but also to many other consequences of immune challenges, including other post-infectious syndromes. It's not only Covid that causes long-term cognitive and other kinds of neurological and neuropsychiatric consequences. We saw this after the influenza pandemic in 1918. We've seen it after many other kinds of infectious challenges and it's important as we prepare for the next pandemic for the next global health challenge that we understand how the long-term consequences of an immune response to a particular pathogen play out.Eric Topol (15:58):No question and that I guess also would include myalgic encephalomyelitis and all the other post-infectious post viral syndromes that overlap with this. Now to switch gears, because that work is just by itself extraordinary but now there's this other field that you are a principal driver, leader, and that is cancer neuroscience. I didn't even know they had boards in neuro-oncology. I thought neurology was enough, but you got board certified in that too. This field is just exploding of interest because of the ability for cancer to cells to hijack neurons and neural circuits, which I guess the initial work goes way back but more recently, the fact that gliomas were just electrically charged. And so maybe you can frame this because this has not just amazing biology, but it's also introducing all sorts of therapeutic opportunities, including many ongoing trials.The Neuroscience of CancerMichelle Monje (17:08):Yes, yes and thank you for asking me about it. It's certainly one of my favorite things to think about, and perhaps as a bridge between the cognitive impairment that occurs after Covid and other inflammatory challenges and the neuroscience of cancer. I'll just highlight that maybe the common theme is it's important to understand the way cells talk to each other and that these sort of molecular conversations are happening on multiple scales and in unexpected ways, and they shape pathophysiology in a very important way. So continuing on that theme, we've known for many, many years, for decades in fact, that the nervous system and its activity shapes the development of the nervous system and actually it doesn't just shape the development of the nervous system where perhaps it's intuitive that the activity within the nervous system might sculpt the way that it forms, but it turns out that innervation is critical for development broadly, that innervation is necessary for organogenesis and that this is becoming clear in every organ that's been studied.(18:15):And so it stands to reason given that kind of perspective on the role that neuronal activity plays in normal development, plasticity, homeostasis, and regeneration of many different tissues, that the activity of the nervous system and those principles can be hijacked in the context of cancer, which is in many ways a disease of dysregulated development and regeneration. And so, I'm a neuro oncologist, I take care of children with a very terrible form of brain cancer called high-grade glioma and the most common form of high-grade glioma in kids occurs in the brain stem, it's called diffuse intrinsic pontine glioma (DIPG). It's really the worst disease you can imagine and understanding it has been the need to understand and treat it has been a guiding principle for me. And so, taking a big step back and trying to wrap my arms around the biology of these terrible high-grade gliomas like glioblastoma, like diffuse intrinsic pontine glioma, I wondered whether nervous system activity might influence cancer the way that it influences normal development and plasticity.(19:23):And as soon as we started to leverage tools of modern neuroscience like optogenetics to ask those questions to modulate the activity of neurons in a particular circuit and see how that influences cancer proliferation and growth, it was clear how very important this was, that active neurons and various subtypes very robustly drives the growth of these brain cancers. And so trying to understand the mechanisms by which that occurs so that we can target them therapeutically, it's become clear that the tumors don't just respond to activity regulated growth signals. They do. There are those paracrine factors, but that in brain cancer, the cancers actually integrate into the neural circuits themselves. That there are bonafide electrophysiological functional synapses that form between various types of neurons and high-grade glioma cells. We're discovering the same can occur in brain metastases from different organs, and that this principle by which neuronal activity drives the cancer is playing out in other tissues.(20:32):So right when we made these discoveries about glioma within this few years, discoveries were made in prostate cancer, in gastric cancer, colon cancer, skin cancer, pancreatic cancer. It seems that innervation is critically important for those tumor, and not just for their growth, but also for invasion metastasis, even initiation in diseases that are driven by particular oncogenes. There's an intersection between the power of those oncogenes to cause the cancer and the necessary environment for the cancer to form and that appears to also be regulated by the nervous system in very powerful ways. So, the exciting thing about recognizing this relatively unsettling feature of cancers is that as we understand it, the neuroscience of cancer becomes an entirely new pillar for therapy to combine with immunotherapy and more traditional cytotoxic therapies and we've been missing it until now. And so the opportunity exists now to leverage medicines that were developed for other reasons, for indications in neurology and cardiology and psychiatry medicines that target neurotransmitter receptors and ion channels that it turns out have a role in some forms of cancer. Now, each cancer has its own biology, so different types of neurons, different neurotransmitters, different neuropeptides play specific roles in that tissue context, but the principle is the same and so as we understand each cancer, we can start to understand what neuroscience inspired medicines we might leverage to better treat these tumors.Rewriting the Hallmarks of CancerEric Topol (22:17):Yeah, I mean it's amazing as a cardiologist to think that beta blockers could be used to help people with cancer and of course there are trials and some studies and particular cancers in that. One of the things that people maybe not outside of oncology don't follow these papers about hallmarks of cancer. There's been two editions, major editions of the hallmarks of cancer, and recently in the journal of cancer Cell, Douglas Hanahan and you wrote a classic about that the hallmarks need to be revised to include neuroscience. Maybe you could elaborate on that because it seems like this is a missing frontier that isn't acknowledged by some of the traditional views of cancer.Michelle Monje (23:08):Absolutely. So I think number one, I want to just give a shout out to Doug Hanahan and the role that the hallmarks of cancer, which is a review article that he wrote and has become sort of the Bible, if you will, of cancer biology really laying out common principles across cancer types that have provided a framework for us to understand this complex and diverse heterogeneous set of diseases. And so it was very exciting when he reached out and asked if I wanted to write this perspective, culminating nervous system interactions, neuroscience interactions as an emerging hallmark of cancer and as we examine them from that, we examine the neuroscience of cancer from that heuristic set of principles, this framework of principles of cancer biology, it's clear that there is a neural influence on the vast majority of them. We now understand from this exciting and burgeoning field that the nervous system can regulate cancer unregulated proliferation.(24:17):It promotes proliferation and growth. It promotes invasion and metastasis. It alters the immune microenvironment. It can both promote pro-tumour inflammation through neurotransmitter signaling. It can also help to modulate anti-tumor immunity. The crosstalk between immune cells, cancer cells and the nervous system are complex, profound, and I would argue incredibly important for immunotherapeutic approaches for cancer. At the same time that there are these diverse effects of the nervous system on cancer, cancer also influences the nervous system. And so, there's really this bidirectional crosstalk happening by which neurons in an activity dependent way, either in short range local neurons or in long range down a nerve or across a circuit, promote the pathophysiology of the cancer and you kind of know it's beneficial because the cancer does many different active things to increase innervation of the tumor. There is in a variety of different tissue context and disease states, elaboration of nervous system interactions through cancer derived either axonogenic or synaptogenic factors secretion, the nervous system remodels the nerves. It remodels the neural circuits to increase the connectivity of the nervous system with the cancer, and also to increase the activity of the nerves to increase the excitability of a neuron. And this contributes to not only driving the cancer, but to many of the really important symptoms that patients face with cancer, including tumor associated seizures as well as cancer associated pain.Eric Topol (26:07):Yeah, I mean this is actually so unusual to see a whole another look at what cancer is about. I mean, this is about as big a revision of thinking as I've seen at least in many, many years. The fact that you pulled this together about the new hallmarks also made me wonder because a number of years ago we went through this angiogenesis story whereby like this cancer can hijack blood vessels and promote it to growth. As you know very well, a lot of these anti-angiogenic efforts didn't go that well. That is they maybe had a small impact overall, but they didn't change the field in terms of success of therapy. I wonder if this is going to play out very differently. What are your thoughts about that? There's lots of shots on goal here and the trials have sprouted out very quickly to go after this.Michelle Monje (27:12):Yeah. I think it's important to recognize various microenvironmental effects on a cancer, including the nervous system effects as one piece of a puzzle that we need to put together in order to effectively treat the disease and I think to effectively treat a particularly very aggressive cancers, we need to hit this from multiple angles. Effective strategies will need to include targeting cell intrinsic vulnerabilities of the cancers as most traditional and targeted therapies are focused on doing right now together with decreasing the strong growth and metastasis influencing effects of the nervous system. I think that's one pillar of therapy that we really have been missing and that represents an important opportunity as well as leveraging the power of the immune system, which perhaps will only work optimally, particularly for solid tumors if you also address the nervous system influences on immune cells. And so I think that it's part of a holistic approach to effective therapy for tumors.(28:21):We have so far failed to treat with single agent or one dimensional kinds of approaches. We need to target not only the cell intrinsic vulnerabilities, the immunotherapeutic opportunities, and the nervous system mechanisms that are influencing all of that in really important ways. So I think it's important to design clinical research in the context of cancer neuroscience with that holistic view in mind. We don't think one strategy is going to be curative for difficult to treat tumors. I don't think that blocking neuron to glioma synapses in glioblastoma and DIPG will alone be sufficient but I do think it may be necessary for other therapies to work.Eric Topol (29:01):Yeah, I think that a perspective of in combination is extremely important. Now the overall, this a big fixation, if you will, about revving up immunotherapies various ways to do that. We'll talk about that in a moment, but without attention to the neurogenic side of this, that might be a problem. Now that gets me to the tumor type that you have put dedicated effort, which is this pediatric pontine tumor, which is horrendous, invading the brainstem and you've even done work with engineering T cells go after that. So you cover all the bases here. Can you tell us about where that stands? Because if you can prevail over that, perhaps that's one of the most challenging tumors of people there is.Diffuse Intrinsic Pontine GliomaMichelle Monje (29:54):Yeah, absolutely. So just a few words about this tumor, for those who don't know, diffuse intrinsic pontine glioma and other related tumors that happen in the thalamus and the spinal cord are the leading cause of brain tumor related death in kids. This is a universally fatal tumor type that tends to strike school age children and it's the worst thing I've ever seen in medicine. I mean, it really has been something that since I saw in medical school, I just have not been able to turn away from. And so studying it from many different perspectives, both the cell intrinsic vulnerabilities, the microenvironmental opportunities for therapy, and also the immunotherapeutic opportunities, it became clear to me that for a cancer that diffusely infiltrates the nervous system forms synapses with a circuit that it is invading and integrates into those circuits in the brainstem and spinal cord, that the only way to really effectively treat it would be a very precise and powerful targeted approach.(30:55):So immunotherapy was a very attractive set of approaches because in the best case, you have an engineered T cell or other immune cell that can go in and kind of like a special forces agent just find the T cells and disintegrate them from this synaptically integrated circuit that has formed. And so I began to search for cell surface targets on this particular type of cancer and found that one of the antigens for which many immunotherapy tools had already been made because it's prevalent in other kinds of cancer, was very highly expressed on diffuse midline gliomas, including diffuse intrinsic pontine glioma. And so this target, which is a sugar, actually it's a disialoganglioside called GD2, is extraordinarily highly and uniformly expressed on DIPG because the oncogene that drives DIPG and other related tumors, which is actually a mutation in genes encoding histone H3, which causes broad epigenetic dysregulation, strongly upregulates the synthesis genes for GD2.(32:05):And so it's a really ideal immunotherapeutic target on every cell, and it's at extraordinarily high levels. Again, speaking to the importance of collaboration, right when we made this discovery, one of the leaders in chimeric antigen receptor T cell therapy, CAR-T cell therapy named Crystal Mackall at Stanford and her offices is in my building, so I walked over and knocked on the door and said, do you want to work on this together? And so, we've been working together ever since and found that indeed CAR-T cells targeting GD2 cure our mice models, which is something I have never seen. I develop these models and have never seen anything that's effective, but it's always easier to help a mouse than to help a person and so we knew that the clinical translation would be challenging. We also knew that it would require intentionally causing inflammation in the brainstem that's already compromised neurocritical care.(33:07):I'm going to not use the word nightmare, but it's a set of challenges that we had to think about really carefully. We spent a lot of time and collaborated with our neurocritical care colleagues, our neurosurgical colleagues, and developed a protocol that had many, we anticipated this neurotoxicity of causing inflammation in the brain stem and we had many safety measures built in an anticipatory way, gave the therapy only in the intensive care unit and had many safeguards in place to treat anticipated hydrocephalus and other consequences of inducing inflammation in this particular region of the nervous system. Over the last four years, we began this trial at the beginning of the pandemic in June 2020 so that was its own unique set of challenges. We've seen some really incredibly exciting promising results we've presented. We've published some of our early experience, we're getting ready to present the larger experience.(34:14):And we've presented this at meetings. We've seen some kids go from wheelchair bound to walking in a matter of weeks. It's been just incredible and reduced to nearly nothing. Other kids have had less robust responses the therapy has really helped some kids, and it's failed others. And so we're working very hard right now to understand what factors affect this heterogeneity and response so that we can achieve durable and complete responses for every kid. I will tell you that my leading hypothesis right now is that it is the intersection of the immuno-oncology with the neuroscience that is modulating the response. Certainly, there are immune suppressive mechanisms, but there's also, I think, really important influences of neurotransmitters and neuropeptides on the immune response against central nervous system cancers in the central nervous system and so we're working hard to understand that crosstalk and develop strategies to optimize this promising therapy.(35:19):But it really has been one of the highlights of my professional life to see kids with DIPG and spinal cord diffuse midline gliomas get better even for a while, something I hoped at some point in my career to ever see and having seen it now so frequently in our trial patients, I'm really hopeful that this approach will be part of the answer. I'm hopeful for the future of immuno-oncology for solid tumors in general. I think when we understand the tumor microenvironment, we will be able to leverage these really powerful therapies in a better way.A Couple of Notable Neuroscientists!Eric Topol (35:58):Wow. Yeah, I mean, if anybody was to try to crack the case of one of the most challenging cancers ever seen, you would be that person. Now, speaking of collaboration, I didn't know this until I was getting ready to have the conversation with you, but your husband, Karl Deisseroth is like the optogenetics father. He is another exceptional rarefied leader in neuroscience. So, do you collaborate with him?Michelle Monje (36:35):We do collaborate, and in fact, so I met Karl when I was a medical student, and he was an intern in psychiatry so we go back a fair ways. We're both MD PhD students at Stanford, and we've been collaborating for many, many years in many different ways both in the clinic, I met him when I was a sub in neurology, and he was the psychiatry intern on neurology. We collaborated when he was a postdoc, and I was a graduate student on some neurobiological studies. We have four children. I have one stepson and four children that I can take full credit for and so we collaborated on five kids. For a while I really wanted, because he is such an amazing scientist, he's such a thought leader in neuroscience, as I started my own independent laboratory, I wanted to not be entirely in his shadow and so I did make it a point to do, I used optogenetics, but I took the course and bought the tools and did it all myself. I did the last questions at the dinner, but I really wanted to be kind of independent in the beginning. Now that my career and my laboratory is a bit more established, we are formally collaborating on some studies because he's a brilliant guy.Eric Topol (38:01):I think that you fit into that category too, and a bit more established is maybe the biggest understatement I've heard in a long time. The body of work you've done already at a young age is just beyond belief and you're on a tear to have big impact and many across the board. As you said, many things that you're learning about the brain with all of its challenges will apply to cancer, generally will apply to hopefully someday a treatment that's effective for Long Covid affects the brain and so many other things. So Michelle, I'm so grateful to have had this conversation. You are an inspirational force. You've covered a lot of ground in a short time and between you and your husband, I don't know that that's got to be the most dynamic duo of neuroscience that exists on the planet, in the human species, I guess. I just can't imagine what those kids of yours are going to do when they grow up.Michelle Monje (39:07):I'm biased, but they're pretty great kids.Eric Topol (39:10):Well, thank you for this and I think the folks that I get to listen to this will certainly get charged up. They'll realize the work that you're doing and the people you collaborate with and making cold calls to people. That's another story in itself that how you can get transdisciplinary efforts when you just approach somebody who's doing some good work. Another lesson just kind of hidden in our discussion. Thanks very much.Michelle Monje (39:40):Oh, thank you. It's wonderful to talk with you, Eric.*******************************************************Please share if your found this podcast informative Get full access to Ground Truths at erictopol.substack.com/subscribe

Jim Collins, leading biomedical engineer, discusses the groundbreaking discovery of a new structural class of antibiotics using AI. They explore using deep learning to analyze molecular structures and finding potent antibiotics like Halicin and Salicin. The podcast also covers the use of graph neural networks to study molecule binding properties, the audacious Antibiotics AI Project, and the challenges in antibiotic development.

Katalin Karikó, a scientist who overcame obstacles and oppression, discusses her journey to make a meaningful discovery, from facing rejection and dismissal to winning the Nobel Prize. Topics include the importance of identifying anomalies in research, challenges faced in promoting mRNA, the broad impact of her discovery, and the potential of mRNA as a versatile platform.

Neurologist and psychiatrist Jonathan Howard discusses the anti-vaccine movement, challenges faced during the COVID-19 pandemic, and the importance of vaccination. Topics include the Great Barrington Declaration, COVID vaccine efficacy against variants, record-keeping in medical statements, combating misinformation, and vaccine challenges.

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