Ground Truths

If there’s one person you’d want to talk to about immunology, the immune system and Covid, holes in our knowledge base about the complex immune system, and where the field is headed, it would be Professor Iwasaki. And add to that the topic of Women in Science. Here’s our wide-ranging conversation.A snippet of the video, Full length Ground Truths videos are posted here and you can subscribe. Ground Truths is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Transcript with many external link and links to the audio, recorded 30 April 2024 Eric Topol (00:06):Hello, it's Eric Topol and I'm really thrilled to have my friend Akiko Iwasaki from Yale, and before I start talking with Akiko, I just want to mention there aren't too many silver linings of the pandemic, but one for me was getting to know Professor Iwasaki. She is my go-to immunologist. I've learned so much from her over the last four years and she's amazing. She just, as you may know, she was just recently named one of the most influential people in the world by TIME100. [and also recognized this week in TIME 100 Health]. And besides that, she's been elected to the National Academy of Medicine, National Academy of Sciences. She's the president of the American Association of Immunologists and she's a Howard Hughes principal investigator. So Akiko, it's wonderful to have you to join into an extended discussion of things that we have of mutual interest.Akiko Iwasaki (01:04):Thank you so much, Eric, for having me. I equally appreciate all of what you do, and I follow your blog and tweets and everything. So thank you Eric.Eric Topol (01:14):Well, you are a phenom. I mean just, that's all I can say because I think it was so appropriate that TIME recognize your contributions, not just over the pandemic, but of course throughout your career, a brilliant career in immunology. I thought we'd start out with our topic of great interest on Long Covid. You've done seminal work here and this is an evolving topic obviously. I wonder what your latest thoughts are on the pathogenesis and where things are headed.Long CovidAkiko Iwasaki (01:55):Yeah, so as I have been saying throughout the pandemic, I think that Long Covid is not one disease. It's a collection of multiple diseases and that are sort of ending up in similar sets of symptoms. Obviously, there are over 200 symptoms and not everyone has the same set of symptoms, but what we are going for is trying to understand the disease drivers, so persistent viral infection is one of them. There are overwhelming evidence for that theory now, all the way from autopsy and biopsy studies to looking at peripheral blood RNA signatures as well as circulating spike protein and nucleocapsid proteins that are detected in people with Long Covid. Now whether that persistent virus or remnants of virus is driving the disease itself is unclear still. And that's why trials like the one that we are engaging with Harlan Krumholz on Paxlovid should tell us what percentage of the people are suffering from that type of driver and whether antivirals like Paxlovid might be able to mitigate those. If I may, I'd like to talk about three other hypotheses.Eric Topol (03:15):Yeah, I'd love for you to do that.Akiko Iwasaki (03:18):Okay, great. So the second hypothesis that we've been working on is autoimmune disease. And so, this is clearly happening in a subset of people, again, it's a heterogeneous disease, but we can actually not only look at reactogenicity of antibodies from people with Long Covid where we can transfer IgG from patients with Long Covid into an animal, a healthy animal, and really measure outcomes of a pathogenesis. So that's a functional evidence that antibodies in some people with Long Covid is really actually causing some of the damages that are occurring in vivo. And the third hypothesis is the reactivation of herpes viruses. So many of us adults have multiple latent herpes virus family members that are just dormant and are not really causing any pathologies. But in people with Long Covid, we're seeing elevated reactivation of viruses like Epstein-Barr virus (EBV) or Varicella-zoster virus (VZV) and that may again be just a signature of Long Covid, but it may also be driving some of the symptoms that people are suffering from.(04:32):So that's again, we see the signature over and over, not just our group, but multiple other groups, Michael Peluso's group, Jim Heath, and many others. So that's also an emerging evidence from multiple groups showing that. And finally, we think that inflammation that occurs during the acute phase can sort of chronically change some tissue tone. For instance, in the brain with Michelle Monje’s team, we developed a sort of localized mild Covid model of infection and showed that changes in microglia can be seen seven weeks post infection even though the virus is completely gone. So that means that inflammation that's established as a result of this initial infection can have prolonged sequence and sequela within the person and that may also be driving disease. And Eric, the reason we need to understand these diseases separately is because not only for diagnostic purposes, but for therapeutic purposes because to target a persistent virus is very different approach from targeting autoantibodies, for example.Eric Topol (05:49):Well, that's great. There's a lot to unpack there as you laid out four distinct paths that could result in the clinical syndrome and sequelae. I think you know I had the chance to have a really fun conversation with Michelle about their joint work that you've done, and she reminded me how she made a cold call to you to start as a collaboration, which I thought was fantastic. Look what that yielded. But yeah, this is fascinating because as I think you're getting at is that it may not be the same pathogenesis in any given individual so that all these, and even others might be operative. I guess maybe I first delve into the antibody story as you're well aware, we see after people get Covid a higher rate of autoimmune diseases crop up, which is really interesting because it seems to rev up self-directed immune response. And this I think many people haven't really noted yet, although obviously you're well aware of this, it's across all the different autoimmune diseases, connective tissue disease, not just one in particular. And it's, as you say, the idea that you could take the blood from a person suffering from Long Covid and give it to an experimental animal model and be able to recapitulate some of the abnormalities, it's really pretty striking. So the question I guess is if you were to do plasmapheresis and try to basically expunge these autoantibodies, wouldn't you expect people to have some symptomatic benefit pretty rapidly or is it just that the process is already far from the initiating step?Akiko Iwasaki (07:54):That's a great question. Plasmapheresis may be able to transiently improve the person if they're suffering from these autoantibody mediated diseases. People have reported, for example, IVIG treatment has dramatically improved their symptoms, but not in everybody. So it's really critical to understand who's suffering from this particular driver and appropriately treat those people. And there are many other very effective therapies in autoimmune disease field that can be repurposed for treating these patients as well.Eric Topol (08:34):The only clinical trial that has clicked so far, interestingly, came out of Hong Kong with different types of ways to manipulate the gut microbiome, which again, you know better than me is a major modulator of our immune system response. What are your thoughts about taking advantage of that way to somehow modulate this untoward immune response in people with this condition?Akiko Iwasaki (09:07):Yeah, so that is an exciting sort of development, and I don't mean to discount the importance of microbiome at all. It's just the drivers that are mentioning are something that can be directly linked to disease, but certainly dysbiosis and translocation of metabolites and microbiome itself could trigger Long Covid as well. So it's something that we're definitely keeping our eyes on. And as you say, Eric, the immune system is in intimate contact with the gut microbiome and also the gut is intimate contact with the brain. So there's a lot of connections that we really need to be paying attention to. So yeah, absolutely. This is a very exciting development.Eric Topol (09:57):And it is intriguing of course, the reactivation of viruses. I mean, we’ve learned in recent years how important EBV is in multiple sclerosis (MS). The question I have for you on that pathway, is this just an epiphenomena or do you actually think that could be a driving force in some people?Akiko Iwasaki (10:19):Yeah, so that's really hard to untangle in people. I mean, David Putrino and my team we're planning a clinical trial using Truvada. Truvada obviously is an HIV drug, but it has reported antiviral activity to Epstein-Barr virus (EBV) and others. So potentially we can try to interrogate that in people, but we're also developing mouse models that can sort of recapitulate EBV like viral reactivation and to see whether there's any sort of causal link between the reactivation and disease process.Eric Topol (10:57):Right now, recently there's been a bunch of anecdotes of people who get the glucagon-like peptide one (GLP-1) drugs which have a potent anti-inflammatory, both systemic and in the brain. I'd love to test these drugs, but of course these companies that make them or have other interests outside of Long Covid, do you think there's potential for a drug like that?Akiko Iwasaki (11:23):Yeah, so those drugs seem to have a lot of miraculous effects on every disease. So obviously it has to be used carefully because many people with Long Covid have issues with liver functions and other existing conditions that may or may not be conducive to taking those types of GLP-1 agonists. But in subset of people, maybe this can be tried, especially due to the anti-inflammatory properties, it may benefit again, a subset of people. I don't expect a single drug to cure everyone. That would be pretty amazing, but unlikely.Eric Topol (12:09):Absolutely. And it's unfortunate we are not further along in this whole story of clinical trials, testing treatments and applauding your efforts with my friend Harlan there to get into the testing which we had hoped RECOVER was going to do with their more than billion dollars or allocation, which didn't get us too far in that. Now before we leave Long Covid, which we could speak about for hours, I mean it's so darn important because so many people are really out there disabled or suffering on a daily basis or periodically they get better and then get worse again. There's been this whole idea that, oh, it's going away and that reinfections don't pose a threat. Maybe you could straighten that story out because I think there seems to be some miscues about the risk of Long Covid even as we go along with the continued circulating virus.Akiko Iwasaki (13:11):Right, so when you look at the epidemiological evidence of Long Covid, clearly in the beginning when we had no vaccines, no antivirals, no real good measure against Covid, the incident of developing Long Covid per infection was higher than a current date where we do have vaccines and Omicron may have changed its property significantly. So if you compare, let's say the Delta period versus Omicron period, there seems to be a reduced risk per infection of Long Covid. However, Omicron is super infectious. It's infected millions of people, and if you look at the total number of people suffering from Long Covid, we're not seeing a huge decline there at all because of the transmissibility of Omicron. So I think it's too early for us to say, okay, the rates are declining, we don't need to worry about it. Not at all, I think we still have to be vigilant.(14:14):We need to be up to date on vaccines and boosters because those seem to reduce the risk for Long Covid and whether Paxlovid can reduce the rate of Long Covid at the acute phase for the high risk individual, it seems to be yes, but for people who are not at high risk may or may not be very effective. So again, we just need to be very cautious. It's difficult obviously, to be completely avoiding virus at this time point, but I think masking and anything you can do, vaccination boosters is going to be helpful. And a reinfection does carry risk for developing Long Covid. So that prior infection is not going to prevent Long Covid altogether, even though the risk may be slightly reduced in the first infection. So when you think about these risks, again we need to be cognizant that reinfection and some people have multiple infections and then eventually get Long Covid, so we're just not safe from Long Covid yet.Nasal Vaccines and Mucosal ImmunityEric Topol (15:24):Right. No, I think that's the problem is that people have not acknowledged that there's an ongoing risk and that we should continue to keep our guard up. I want to applaud you and your colleagues. You recently put out [Yale School of Public Health] this multi-panel about Covid, which we'll post with this podcast that gave a lot of the facts straight and simple diagrams, and I think this is what you need is this is kind of like all your threads on Twitter. . They're always such great educational ways to get across important information. So now let's go onto a second topic of great mutual interest where you've also been a leader and that's in the mucosal nasal vaccine story. I had the privilege of writing with you a nice article in Science Immunology back in 2022 about Operation Nasal Vaccine, and unfortunately we don't have a nasal vaccine. We need a nasal vaccine against Covid. Where do we stand with this now?Akiko Iwasaki (16:31):Yeah, so you're right. I mean nasal vaccines, I don't really know what the barrier is because I think the preclinical models all support the effectiveness against transmission and infection and obviously disease. And there is a White House initiative to support rapid development of next generation vaccine, which includes mucosal vaccine, so perhaps that's sort of pushing some of these vaccine candidates forward. You're probably more familiar than me about those kinds of events that are happening. But yeah, it's unfortunate that we don't have an approved mucosal booster vaccine yet, and our research has shown that as simple as a spray of recombinant spike protein without any adjuvants are able to restimulate immune response and then establish mucosal immunity in the nasal cavity, which goes a long way in preventing infection as well as transmission. So yeah, I mean I'm equally frustrated that things like that don't exist yet.The Neomycin and Neosporin SurpriseEric Topol (17:52):Well, I mean the work that you and many other groups around the world have published on this is so compelling and this is the main thing that we don't have now, which is a way to prevent infection. And I think most of us would be very happy to have a spray that every three or four months and gave us much higher levels of protection than we're ever going to get from shots. And your whole concept of prime and spike, I mean this is something that we could have had years ago if there was a priority, and unfortunately there never has been. Now, the other day you came with a surprise in a paper on Neomycin as an alternate or Neosporin ointment. Can you tell us about that? Because that one wasn't expected. This was to use an antibiotic in a way to reduce Covid and other respiratory virus.Akiko Iwasaki (18:50):Right. So yeah, that's a little known fact. I mean, of course widespread use of antibiotics has caused some significant issues with resistance and so on. However, when you look at the literature of different types of antibiotics, we have reported in 2018 that certain types of antibiotics known as aminoglycoside, which includes Neosporin or neomycin, has this sort of unintended antiviral property by triggering Toll-like receptor 3 in specialized cell types known as conventional dendritic cell type 1. And we published that for a genital herpes model that we were working on at the time. But because it's acting on the host, the Toll-like receptor 3 on the host cell to induce interferon and interferon stimulated genes to prevent the replication of the virus, we knew that it could be pan-viral. It doesn't really matter what the virus is. So we basically leverage that discovery that was made by a postdoc Smita Gopinath when she was in the lab to see if we can use that in the nasal cavity.(20:07):And that's what Tianyang Mao, a former graduate student did, in fact. And yeah, little spray of neomycin in the nose of the mice reduce this infection as well as disease and can even be used to treat shortly after the infection disease progress and using hamster models we also showed that hamsters that are pretreated with neomycin when they were caged with infected hamsters, the transmission rate was much reduced. And we also did with Dr. Charles Dela Cruz, a small clinical trial, randomized though into placebo and Neosporin arms of healthy volunteers. We asked them to put in a pea size amount of Neosporin on a cotton swab into the nose, and they were doing that twice a day for seven days. We measured the RNA from the nose of these people and indeed see that more than half the participants in the Neosporin group had elevated interferon stimulated genes, whereas the control group, which were given Vaseline had no response. So this sort of shows the promise of using something as generic and cheap as Neosporin to trigger antiviral state in the nose. Now it does require a much larger trial making sure that the safety profiles there and effectiveness against viral infection, but it's just a beginning of a story that could develop into something useful.New Frontiers in Immunology and Tx CellsEric Topol (21:51):Yeah, I thought it was fascinating, and it does bring up, which I think has also been underdeveloped, is our approaches for interferon a frontline defense where augmenting that, just getting that exploiting the nasal mucosa, the entry site, whether it be through that means or of course through even more potent a nasal vaccine, it's like a missing, it's a hole in our whole defense of against this virus that's led to millions of people not just dying, but of course also sick and also with Long Covid around the world. So I hope that we'll see some progress, but I thought that was a really fascinating hint of something to come that could be very helpful in the meantime while we're waiting for specific nasal vaccines. Now added to all these things recently, like last week you published a paper in Cell with your husband who's in the same department, I think at Yale. Is that right? Can you tell us about that and this paper about the whole new perspectives in immunology?Akiko Iwasaki (23:05):Yeah, so my husband Ruslan Medzhitov is a very famous immunologist who's in the same department, and we've written four or five review and opinion pieces together over the years. This new one is in Cell and it's really exploring new perspectives in immunology. We were asked by the editors to celebrate the 50th anniversary of the Cell journal with a perspective on the immune system. And the immune response is just a beautiful system that is triggered in response to specific pathogens and can really provide long-term or even sometimes lifelong immunity and resistance against pathogens and it really saves our lives. Much has been learned throughout the last 20, 30 years about the innate and adaptive immune system and how they're linked. In this new perspective, we are trying to raise some issues that the current paradigm cannot explain properly, some of the mysteries that are still remaining in the immune system.(24:22):And we try to come up with new concepts about even the role of the immune system in general. For instance, is the immune system only good for fighting pathogens or can it be repurposed for conducting normal physiology in the host? And we came up with a new subset of T-cells known as, or we call it Tx cells, which basically is an interoceptive type of T-cells that monitor homeostasis in different tissues and are helping with the normal process of biology as opposed to fighting viruses or bacteria or fungi. But these cells, when they are not appropriately regulated, they are also the source of autoimmune diseases because they are by design reactive against auto antigens. And so, this is a whole new framework to think about, a different arm of the immune function, which is really looking inside of our body and not really fighting against pathogens, but we believe these cells exist, and we know that the counterpart of Tx cells, which is the T regulatory cells, are indeed well known for its physiological functions. So we're hoping that this new perspective will trigger a new set of approaches in the field to try to understand this interceptive property of T-cells.Eric Topol (25:59):Yeah, well, I thought it was fascinating, of course, and I wanted to get into that more because I think what we're learning is this immune system not only obviously is for cancer whole. We're only starting to get warmed up with immunotherapy where checkpoint inhibitors were just the beginning and now obviously with vaccines and all these different ways that we can take the CAR-T cells, engineered T-cells, take the immune system to fight cancer and potentially to even use it as a way to prevent cancer. If you have these, whether it's Tx or Tregs or whatever T-cells can do this. But even bigger than that is the idea that it's tied in with the aging process. So as you know, again, much more than I do, our senescent immune cells are not good for us. And the whole idea is that we could build immune resilience if we could somehow figure out these mysteries that you're getting at, whereby we get vulnerable just as we were with Covid. And as we get older, we get vulnerable to not just infections, but everything going wrong, whether it's the walls of our arteries or whether it's the cancer or the immunity that's going on in our brain for Alzheimer's and neurodegenerative diseases. How can we fix the immune system so that we age more healthilyThe Immune System and Healthy Aging Akiko Iwasaki (27:37):Oh yeah. A lot of billionaires are also interested in that question and are pouring money into this question. It's interesting, but when you think about the sort of evolutionary perspective, we humans are only living so long. In the very recent decades, our life expectancy used to be much shorter and all we had to survive was to reproduce and generate the next progeny. But nowadays, because of this amazing wealth and health interventions and food and everything else, we're just living so much longer than even our grandparents. The immune system didn't evolve to deal with such one to begin with. So we were doing fine living up to 30 years of age or whatever. But now that we're living up to a hundred years, the immune system isn't really designed to keep up with this kind of stressors. But I think you're getting at a very important kind of more engineering questions of how do we manipulate the immune system or rejuvenate it so that we can remain healthy into the later decades? And it is well known that the immune system itself ages and that our ability to produce new lymphocytes, for example, decline over time and thymus that is important for T-cell development shrinks over time. And so anatomically it's impossible to help stop that process. However, is there a way of, for example, transferring some factors or engineering the immune cells to remain healthy and even like hematopoiesis itself can be manipulated to perhaps rejuvenate the whole immune system in their recent papers showing that. So this is a new frontier.Eric Topol (29:50):Do you think that some point in the future, we'll ex vivo inject Yamanaka factors into these cell lines and instead of this idea that you know get young plasma to old folks, and I mean since we don't know what's in there and it doesn't specifically have an effect on immune cells, who knows how it's working, but do you foresee that that might be a potential avenue going forward or even an in vivo delivery of this?Akiko Iwasaki (30:22):Yeah, it's not impossible, right? There are really rapidly evolving technologies and gene therapies that are becoming online. So it's not impossible to think about engineering in situ as you're suggesting, but we also have to be certain that we are living longer, but also healthy. So we do have to not only just deal with the aging immune system, but preventing neurodegenerative diseases and so on. And the immune system may have a role to play there as well. So there's a lot of, I mean, I can't think of a non-genetically mediated disease that doesn't involve the immune system.Eric Topol (31:03):Sure. No, I mean, it's just, when I think about this, people keep talking about the digital era of digital biology, but I actually think of it more as digital immunobiology, which is driving this because it's center stage and in more and more over time. And the idea that I'm concerned about is that we could rejuvenate the relevant immune cells or the whole immune response, but then it's such a delicate balance that we could actually wind up with untoward, whether it's autoimmune or overly stimulated immune system. It's not such a simple matter, as I'm sure you would agree. Now, this gets me to a broader thing which you've done, which is a profound contribution in life science and medicine, which is being an advocate for women in science. And I wonder if you could speak to that because you have been such a phenomenal force propelling the importance of women in science and not just doing that passively, but also standing up for women, which is being an activist is how you get things to change. So can you tell us about your thoughts there?An Activist for Women in ScienceAkiko Iwasaki (32:22):Yeah, so I grew up in Japan, and part of the reason I left Japan at the age of 16 was that I felt very stifled because of the societal norm and expectation of what a woman should be. And I felt like I didn't have the opportunity to develop my skills as a scientist remaining in Japan. And maybe things have changed over the years, but at the time when I was growing up, that's how I felt. And so, I was very cognizant of biases in society. And so, in the US and in Canada where I also trained, there's a lot less barrier to success, and we are able to do pretty much anything we want, which is wonderful, and that's why I think I'm here. But at the same time, the inequity still exists, even in pay gaps and things like that that are easy to fix but are still kind of insidious and it's there.(33:32):And Yale School of Medicine has done a great job partly because of the efforts of women who spoke up and who actually started to collect evidence for pay gap. And now there's very little pay gap because there's active sort of involvement of the dean and everyone else to ensure equity in the medical school. But it's just a small segment of the society. We really need to expand this to other schools and making sure that women are getting paid equally as men in the same ranks. And also, I see still some sexual harassment or more just toxic environment for people in general in academia. Some PIs get away with a lot of behavior that's not conducive to a healthy environment, so I have written about that as well and how we can have antidotes for such toxic environments. And it really does require the whole village to act on it. It's not just one person speaking up. And there should be measures placed to make sure that those people who does have this tendency of abusive behavior that they can get training and just being aware of these situations and corrective behavior. So I think there's still a lot of work left in academia, but things have obviously improved dramatically over the last few decades, and we are in a very, very good place, but we just have to keep working to achieve true equity.Why Don’t We Have Immunome Check-Ups?Eric Topol (35:25):Well applauding your efforts for that, and I'm still in touch with that. We got a ways to go, and I hope that we'll see steady and even more accelerated and improvement to get to parity, which is what it should be. And I really think you've been a model for doing this. It isn't like you aren't busy with everything else, so to fit that in is wonderful. In closing up, one of the things that I wonder about is our ability to assess back to the immune system for a moment isn't what it should be. That is we do a CBC and we have how many lymphocytes, how many this, why don't we have an immunome, why doesn’t everybody serially have an immune system checkup? Because that would tell us if we’re starting to go haywire and then maybe hunt for reactivated viruses or what’s going on. Do you foresee that we could ever get to a practical immunome as we go forward? Because it seems like it’s a big missing link right now.Akiko Iwasaki (36:33):Yeah, I think that’s a great idea. I mean, I’ll be the first one to sign up for the immunome.Eric Topol (36:40):But I’m depending on you to make it happen.Akiko Iwasaki (36:44):Well, interestingly, Eric, there are lots of amazing technologies that are developed even during the pandemic, which is monitoring everything from antibody reactivity to reactivated viruses to the cytokines to every cell marker you can imagine. So the technologies out there, it’s just I think a matter of having the right set of panels that are relatively affordable because some of these things are thousands of dollars per sample to analyze, and then of course clinical validation, something that’s CLIA approved, and then we can start to, I guess the insurance company needs to also cover this, right? So we need to demonstrate the benefit to health in the long run to be able to afford this kind of immunome analysis. But I think that very wealthy people can already get this done.Eric Topol (37:43):Yeah, well, we want to make it so it's a health equity story, not of course, only for the crazy ones that are out there that are taking 112 supplements a day and whatnot. But it's intriguing because I think we might be able to get ahead of things if we had such an easy means. And as you said during the pandemic, for example, my friends here in La Jolla at La Jolla Immunology did all kinds of T-cell studies that were really insightful and of course done with you and others around the country and elsewhere to give us insights that you didn't get just from neutralizing antibodies. But it isn't something that you can get done easily. Now, I think this immunome hopefully will get us to another level in the future. One of the most striking things I've seen in our space clinically before wrapping up is to take the CD19 CAR T therapies to deplete the B cells of people with lupus, systemic sclerosis and other conditions, and completely stop their autoimmune condition. And when the B cells come back, they're not fighting themselves. They're not self-directed anymore. Would you have predicted this? This seems really striking and it may be a clue to the kind of mastering approaches to autoimmune diseases in the future.Akiko Iwasaki (39:19):Yeah, absolutely. So for multiple sclerosis, for example, where B cells weren't thought to be a key player by doing anti-CD20 depletion, there's this remarkable clinical effects. So I think we can only find the answer experimentally in people when they do these clinical trials and show this remarkable effects. That's when we say, aha, we don't really understand immunology. You know what I mean? That's when we have to be humble about what we think we understand. We really don't know until we try it. So that's a really good lesson learned. And these may be also applicable to people with autoimmune phenotype in Long Covid, right? We may be able to benefit from similar kinds of depletion therapy. So I think we have a lot to learn still.Eric Topol (40:14):Yeah, that's why, again, going back to the paper you just had in Cell about the mysteries and about some new ideas and challenging the dogma is so important. I still consider the immune system most complex one in the body by far, and I'm depending on you Akiko to unravel it, not to put any weight on your shoulders. Anyway, this has been so much fun. You are such a gem and always learning from you, and I can't thank you enough for all the work. And the fact is that you've got decades ahead of you to keep building on this. You've already done enough for many people, many scientists in your career, and I know you'll keep going. So we're all going to be following you with great interest in learning from you on a frequent basis. And I hope we'll build on some of the things we've talked about like a Long Covid treatment, treatments that are effective nasal vaccines, maybe even some dab of Neosporin, and keep on the momentum we’ve had with the understanding of the immune system, and finally, someday achieving the true parity of gender and science. And so, thank you for all that you do.Akiko Iwasaki (41:35):Thank you so much, Eric.************************CreditsHeadshot photo credits by Robert Lisak, Yale School of MedicineMy producer for Ground Truths is Jessica Nguyen, Scripps Research and our technical support for audio/video is by SInjun Balabanoff at Scripps Research.I hope you found the spot informative. Please share itThe Ground Truths newsletters and podcasts are all free, open-access, without ads.Voluntary paid subscriptions all go to support Scripps Research. 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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

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