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

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

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

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