Avoiding, Treating & Curing Cancer | Dr. Alex Marson

We're living in this amazing moment of biology where we can put a gene that encodes something on the surface of tea cells that will make them programmed to search and destroy for cancer cells. Now this is largely known as CART tea cells, chimeriic antigen receptor. This is a receptor that was designed in a lab does not exist in nature. When those tea cells get reinfused into a patient the way that you get like a a blood transfusion, those cars are directed to go against cancers. Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and opthalmology at Stamford School of Medicine. My guest today is Dr. Alex Marson. Dr. Alex Marson is a medical doctor and scientist at the University of California, San Francisco. He is developing new ways to reprogram the immune system to cure cancers. Today we discuss how your immune system works, how autoimmunity works, and how gene editing and other new technologies can be successfully leveraged to defeat childhood and adult cancers. Dr. Dr. Marson is truly one of a kind in his understanding of the clinical aspects of cancer treatment, the science of the immune system, and as you'll soon hear, in explaining the things that genuinely increase your cancer risk, many of which are surprising, and the actionable steps that we can all take to reduce our probability of getting cancer. In addition to the usual factors, smoking, UV light, and environmental toxins such as pesticides, we discuss the actual cancer risks that come from things like eating charred meats, airport scanners, and food additives, and how to gauge your individual level of risk. We also explore gene editing for reversing diseases, which until recently was science fiction, but now is a reality. By the end of today's episode, thanks to Dr. Marson, you'll have the most up-to-date understanding of the state-of-the-art science for cancer prevention and treatment. Knowledge that is certain to impact you or a close friend or family member in your lifetime. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Alex Marson. Dr. Alex Marson, welcome. Andrew, this is the first time that we're going to have a serious discussion about the immune system, cancer, and gene editing technologies on this podcast. So, I'm delighted that you're here. It's also great to see you again. Thank you for having me. Really, really good to see you. It's been a while. Let's start off with the big picture. Uh, how are we doing? How's uh how's biology looking? How's medicine looking? Are we uh are we on the fast track to much better things? Are we going to slog along for another 10 years before we have cures to the many concerns that people have about cancer, Alzheimer's, and the rest? Or are you encouraged by what's happening right now? I think maybe there's some some the general public doesn't quite know how excited biologists are about what's possible. And maybe we've overpromised. Maybe in the past we've said we're on the brink of curing disease and people haven't seen it. But something is materially different right now. And there is a convergence of so many different ways of understanding biology but then not having that stop at understanding but to actually intervene and at the root causes of disease. And over the course of this conversation, I imagine we're going to talk about DNA sequencing, understanding cells, but going all the way to rewriting specific DNA sequences inside of the cells of our immune system. Doing this not one at a time, but testing every gene and understanding pieces of DNA throughout our entire genome to understand what controls our cells. and then being able to take that information and actually do something about it to boost our immune system to go after cancer to balance it for inflammation and autoimmunity. And that doesn't just have to be sort of searching for a pill. All of a sudden, we can actually talk to our own cells and give them instructions in the language of DNA and the language of molecular biology. And in some instances, this is being done with crisper, but it's also being done with lipid nanop particles and vaccines. And we're still inventing new ways of giving these instructions. But all of a sudden, medicine is programming the behavior of cells in a way that's much more directed than was ever conceivable before. Like there's really a step function in what's imaginable and achievable in medicine. Super exciting. Do you think that molecular biology and genetic engineering andor AI are the reasons that things are on this accelerated timeline? Yes is the answer. All of those things I think we can do experiments at a different level of scale. we can generate data and then we have the computational tools in including AI but we have computational sophistication to actually extract insights from massive amounts of data and you know I think historically biology was we were it was an observational science if you especially if you wanted to study things in in humans there wasn't a way to intervene now all of a sudden we're taking human cells we're putting taking them into the lab and making genetic changes is and reading out the consequences and directly being able to observe the effect. And we have all the we have tools to do this with imaging. We have the tools to do this with DNA sequencing. And we can take this all the way into clinical trials and see what are the what are the consequences when we actually go after targeted DNA sequences and make our cells better at treating disease. Would you mind educating us about the immune system a bit? the adaptive and the innate immune system, some of the major cell types, because I think those are going to form the kind of building blocks of our discussions about cancer and and other things today. Our immune system permeates almost every aspect of our health and disease. It is a system really in the sense of it it's involved in every part of our body that has evolved to protect us largely to protect us against infections, viruses, bacteria, fungus. all sorts of foreign invasions and our immune system has developed a balance that is when it's working properly doesn't recognize the cells that are supposed to be in the body but is finely tuned to recognize signs of things that shouldn't be in the body and to eliminate them. I mean at at its core that's that's the the basic job of the immune system to recognize us versus non us. Exactly. And you you talked about the innate versus the adaptive immune system. Largely what we're talking about are white blood cells. We're we're talking about different types of white blood cells that are either inside of tissues or circulating in our bloodstream that go around and play coordinated and specialized roles in sensing when something comes in that is not us that's foreign that shouldn't be there. The innate immune system does it as is sort of thought of as the the first alarm system that something something's wrong. And with the innate immune system, which consists of cells like dendritic cells, macrofasages, these are cells that are going around and they're looking for patterns of things that just generally aren't in human cells. some signs of damage, some signs of things that are just that shouldn't be there in a in a generic way in a healthy human. When those first alarm systems get triggered, all of a sudden these innate immune systems start releasing things. They change their state and they send off an alarm to other cells in the immune system and then they often recruit in the second arm of the immune system that you mentioned, the adaptive immune system. We'll talk a lot about the adaptive immune system today. And the major players in the adaptive immune system are a group of white blood cells that are collectively known as lymphosytes. But we'll talk about B cells and T- cells in particular, which are major groups of of lymphosytes. We've been focused heavily on T- cells. TE- cells play a central role in coordinating the fine-tuning of the immune response. One of the amazing things about the te- cells is that each te- cell naturally in our body. It's one of the few places where each cell will actually have a different piece of DNA that's not inherited in in our germ line sequence. Each tea cell will make its own receptor that is generated largely at random to go and sense something. And those those sensors that get put on the surface of tea cells are there to engage. And if they're engaged, it's a sign that something has has been recognized as foreign. And so we have this incredible diversity of of different T- cell receptors that are have developed on our tea cells. Each one will have a different unique receptor on its surface. Each cell will have a different receptor on its surface. And the the way to think about these receptors is that they're sensors for they're when they're engaged, they send a signal to the T- cell that okay, we found something that that you've been programmed to recognize and program is recognized as far and if it if the immune system is working properly. And are the genes uh that these tea cells make as these receptors uh are those based on experience of the of the organism? Because you said that it doesn't come from the germ line, but we should clarify that the germ line is not about infectious germs in this context. The germline DNA is from the sperm and egg that were your parents. It became you. There's re combination of those genes. And then there's you all um each and all. Um and the tea cells are making genes that neither your parents necessarily expressed nor that you were expected to express except based on what exposure to particular pathogens. Like why do they make certain receptors and not others? Largely random. It actually there's the pieces of DNA at this part of the the DNA actually recombine and get pasted together in in unique ways. So it's probabilistic. It's probabilistic and that's what allows us to have cells that lying there in waiting for things that we've never encountered. If a a a bacteria might come into existence or a virus might come into existence that doesn't even exist now in nature, but we might have tea cells lying there waiting that could be engaged by those proteins on the surface that viruses would introduce. That's incredible. Would you mind mentioning the the role of the thymus? These days I'm hearing more and more about we have a thymus and we lose a thymus. Would it be beneficial if we could keep our thymus around? So thymus is is actually the reason the tea cells are called te- cells is the T stands for thymus and the thymus is an organ that it does sort of shrink as we age but at least in childhood it's it sort of lies by your heart and it is the place where tea cells go in a key place of their education. So they they've have are making these sensors at largely at random and then in the thymus they get cold they get selected and they the ones that by accident are generated that recognize something that is supposed to be in your body if if the T- cell engages a natural target in the thymus those cells will die and so what emerges from the thymus should be and this is not perfect process but should be things that have are have emerged at random but then are selected to remove things that recognize your own body targets. There's sort of a negative selection of the stuff that's you so that your immune system doesn't attack you and it knows you from non you. Yeah, that's exactly right. There's actually both a positive selection and a negative selection. That's exactly the right way to think. The cells get will only emerge from the thymus that if they have a a receptor on their surface that's there. So that's one positive selection, but if it engages with a self target in the thymus, it gets negatively selected. So what comes out are tea cells that are there with sensors in place to recognize things that shouldn't be there. Okay. So your thymus and your tea cells get educated in childhood. Yeah. And that's what you're working with except that the immune system can adapt and make antibodies to things it doesn't recognize. the antibodies come from the from the other type of lymphosy lymphosytes. So now now we can talk about the B cells. B cells are this other type of lymphosy that work in coordination with T- cells and they're the antibbody producing cells. So they actually have a similar process where they're generating different antibodies at random through a similar kind of recombination event. they have their own form of selection that they go through and then those antibodies can then be released into the bloodstream and and are the basis for protection against infections after we get them. I'd like to take a quick break and acknowledge our sponsor, BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online. Now, I've been doing therapy for a very long time and I can tell you that it's a lot like physical workouts. There are days when I want to do it and there are days when I don't want to do it. But when I finish a therapy session, every single time I come away feeling better and knowing that the time was well spent. And typically when I finish a therapy session, I come away with a valuable insight or some new perspective on something that I've been working through. 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You answer those questions and Helix will match you to the ideal mattress for you. For me, that turned out to be the Dusk Dusk mattress. I've been sleeping on a Dusk mattress for more than four years now, and it's been far and away the best sleep that I've ever had. If you'd like to try Helix, you can go to helixleep.com/huberman, take that 2-minut sleep quiz, and Helix will match you to a mattress that's customized for you. Right now, Helix is giving up to 27% off their entire site. Helix has also teamed up with TrueMed, which allows you to use your HSA FSA dollars to shop Helix's award-winning mattresses. Again, that's helixleep.com/huberman to get up to 27% off. What um underlies the sort of efficiency and functioning of the immune system? I I know I and many people are thinking, okay, we hear like our immune system gets activated or our uh our immune system is impaired. Um the one thing that I'm certain uh supports the immune system is great sleep, right? And we just know this. If we don't sleep well or enough, we get sick. Is that because there's a a known impairment of the immune system? I I wonder about this too. I mean, I agree. I've experienced that so many times of being run down and then being being feel experiencing that I'm susceptible to infection, but I I don't actually know the basis of that. I mean, it's kind of amazing how much we don't know about these determinants of of immune health largely because they're often variables that are left out of the the mouse studies that we're doing. We're, you know, we're studying largely steady state uh immune responses in mice. And I I would say we don't haven't done a full exploration yet of all the types of ways that general health impinges on the immune system. I had a someone in my lab a postoc named Sager Bapat who came to my lab with an interest in in in metabolic health and wanted to study the effect of metabolic health on on tea cells and this there's some subgrowing stuff on this but it's another like what what are the determinants of it he did an he did experiments in my lab where he exposed some an allergen something that irritated the skin and caused an allergic type reaction ction in the skin of mice. He did it in mice that were eating a normal mouse diet versus a highfat diet that caused obesity. And what we saw was that it was actually not just a qual a quantitative difference in the immune system, but actually a qualitative difference. The actual type of inflammation, the cell responses were different in in the mice eating a highfat diet. And I think we haven't done enough studies like that where we actually start playing with the variables of life and test them in in a mechanistic way to isolate individual variants. What was interesting there was that the allergic reaction actually looked totally different in the obese mice and if we used surrogates that are for the types of drugs that are being used now to treat severe allergy. So we gave antibodies that block allergic responses. the normal lip diet mice would respond favorably to these. It it they didn't help the the mice that had the obese highfat diet respon response to inflammation and in some cases it actually maybe made it worse. So so I think that there are these these systemic ways I mean clearly we know we our intuition tells us this strongly that systemic health can can feed into our immune responses but I think it's still been underexplored in rigorous ways. I realize I'm asking very top contour type questions for which there probably aren't specific answers, but we all know people that um get sick all the time. Um and we know people who never seem to catch the bugs that everyone else seems to catch. Is there any understanding of what a more robust immune system is at the level? Is it more tea cells? Is it um you know are the the B cells engaged more quickly so they can generate antibodies more quickly? What is it? These are great questions I I that I don't think have full full answers. There are there's been a lot of work on genetic determinance and and there's extreme cases where people have a genetic gap in their immune system where they're really susceptible to something that healthy people should not be susceptible to. And you see that there are certain types of infections that either happen or happen with a different type of severity in people with genetic deficits in c in certain branches of their immune system. And and in some cases you can pinpoint that we just talked about the innate immune response, the adaptive immune response. You can see that certain genetic mutations that people inherit could influence one or multiple branches of that immune responses and the consequences that you that manifests itself with different types of infection. And I suspect that there's some spectrum of that that we see the the really you can diagnose the really strong genetic consequences and then there might be a long tail of more subtle genetic that might be multi multigenic that we don't fully understand and then I'm sure that there's other determinants of health that are just multiffactorial and so it's you know it also becomes this interplay between the health and then what you get exposed to by by your environment. Yeah. Speaking of which, I'm familiar with some studies from Stanford, I believe, where um kids that have no exposure to peanuts get peanut allergies and um careful subtle increasing exposure to peanuts essentially um protects them against peanut allergies. So, is it true that when we're young that exposure to pathogens um and different foods uh gives us a more robust immune system? I think that there's the what we're exposed to and what we develop tolerance for is is critically important during there's some windows of early life that I think are we're particularly susceptible to becoming tolerant and I think if we don't get the proper exposure to certain things all of a sudden our our body can start to be hyper sensitive to them which manifests as allergies now there's this balancing act I think the fear of allergies makes people more more hesitant to expose kids and I think you can it can get into these these dangerous zones of you don't want to expose kids who are going to have a a dangerous allergic response but on the other hand critical early exposure is part of how tolerance is maintained and I I think peanut allergies there there is strong evidence that exposure to peanuts can be beneficial in people who are not yet allergic what's going on with autoimmune conditions is this that the the B cells and T- cells are at probabilistic level that tea cells developed um some reaction so to speak a binding to um cells that we naturally make that they shouldn't have. It's just like it happens. I've always been intrigued by by the idea that when the immune system is really ramped up um people will experience autoimmune like symptoms. I had experienced that as a master's student. I I was working so much and probably not eating enough and drinking so much caffeine back then that I got some kind of funky skin lesion things. I went to the doctor and like, "Oh, you're starting to get some attack of the deeper layers of of your skin. Um, you just need to work a little less." And sure enough, did that trick? It did the trick, you know. But I I was just it made me so keenly aware of how um the immune system will for lack of a better word adapt to conditions and it was trying to keep me healthy and it it overshot the mark basically. I sort of walked you through at a first principle like how things are supposed to work. I told you okay there's this process of generating receptors on the surface of T- cells. Antibodies get generated on B cells. They go through this positive selection and negative selection. That's a delicate balancing act and it doesn't actually work that way in practice. In in practice, TE-C cells escape from the thymus that do recognize our own self antigens and there's actually secondary mechanisms there to block that. But autoimmune diseases emerge when those normal checks fail. This and I think it's a consequence that the immune system has two major responsibilities. It has to be primed to protect us from infections which would be fatal and be strong and recognize this incredible diversity of potential foreign dangerous things that we might experience. But it also has to not recognize our own cells. And it can miss the mark in both ways. And so autoimmune disease manifests in different tissues. If if you if your immune system starts recognizing targets in your joints, it can cause rheumatoid arthritis. If it's in the cells that produce insulin in the pancreas, it causes type 1 or childhood diabetes. Um, if it's the my mileinated cells in the brain, it's multiple sclerosis. So, this is autoimmunity and inflammation of different kinds cause their own pathology. So, we want to the immune system is always these sort of two sides of the coin. Making sure that we're having strong responses to infection. We'll talk about cancer where we want to also strengthen our responses. But for autoimmunity, inflammation, allergies, we want to make sure that like our goal therapeutically in with drugs is to make sure that we make the immune system under control and ideally do it in a targeted way so that you don't have to turn off the whole immune system with blanket immunosuppression, but to do it in a way that just makes you tolerant or not reactive against the things that are being inappropriately targeted by the immune system. Two things that I'd love to understand about the immune system is uh how is it that um an immune response let's say to a cold virus is systemic like like where is the sort of master uh uh controller is it or maybe it's a distributed system that says like okay we need to launch a a bodywide response as opposed to a localized response. I can I can imagine like with a splinter, of course, you're going to get a localized response. It's a little piece of wood or metal and so you're going to get the innate response and you're going to get some pus around it and it'll kind of localize the wound. But when it comes to an invasive virus like the cold virus, uh it overtakes us, right? The production of mucus, we got the headache, like the and I think it's the systemic effect that um that intrigues me so much. like where is the signal to to to launch a systemic versus a localized response in the immune system? How does it determine that? You know, I think some of it depends on on what virus we're talking about, how systemically invasive the the different viruses can be, and some of it can be that the immune system has different levels of, you know, it can have a local response, but the immune system, the cells that we talked about in the immune system, one of their jobs can actually be to secrete things into the bloodstream, things that are essentially chemical signals that something is wrong. major ones are they're called cytoines and they can act locally but they can also have more distributed effects and some of the things that that that the cytoines can do can influence what can cause the development of fever right so you you can have these sort of cascading effects of something being recognized at a particular site in the body then sending distributed signals to the blood that will make us feel sick and you know in some cases there's again this balancing act of maybe a fever gives us some edge in fighting s some some types infection, but it also makes us feel lousy. And so the you know the the immune system is is always walking that I think in sometimes the immune system immune system response to infections is too strong and a lot of the the negative consequence of what we experience is the immune system going too far and having to come back as as the as the as an infection gets under control. Thank you. One of the reasons I asked that is well I hate being sick. Fortunately I don't get sick too often if I take good care which I think is like most people. I think about antibiotics for instance. Antibiotics are amazing. Yeah. I've had a few things where I was like, "Ah, this thing's bothering me." And uh like I had this sinus infection a few years back and I was like, "Ah, this is definitely not a cold." And then they tell you it's not a sinus infection unless I was like, "I have a feeling." Now, I'm not a physician of course, but um it got really bad. And I took antibiotics and within a day I was feeling substantially better. That's great. Many people have such experiences with antibiotics. I realize they can be overprescribed and you can end up with antibiotic resistant infections. That's a concern for sure. But what is the sort of inherent danger of using things like antibiotics the way I described like not in a in a life or death situation to mitigate the duration or the intensity of some sort of infection because surely you're shortcircuiting your immune system's uh ability to eventually just fight that thing off. Like is part of building a robust immune system across your lifespan, allowing your immune system to do the work and going through the misery of being really sick and infected? I don't think so. Great. Okay. Fantastic. Love that answer. Love that answer. I think you probably were exposed and had an immune response. Antibiotics when they're used for bacterial infections that that are susceptible to them are a miracle. And you know, we live in this amazing sliver of human history where we have antibiotics that can cure disease. I mean, I think many of us have had bacterial infections of different kinds, cuts and wounds that would have been deadly in other generations. And we're we're we're the beneficiaries of having antibiotics that work. We are at some risk that if we overuse them, that window of human history might come to an end if we don't continue to replenish new antibiotics. But we gain more and more bacteria that are resistant to antibiotics. Are people developing new antibiotics? It's an underfunded area of medicine because I just hear a moxicil pen. I have a friend over in the UK who's been having some some eye symptoms that um from what I'm learning, we're still learning is likely an infection uh in near the posterior chamber, which just simply means his vision is potentially at risk. Systemic antibiotics are very likely going to save his vision. And so people say, well, antibiotics are bad. Like a hundred years ago, we probably would have just they would have just inucleated the eye, which is be blind, right? So it's I think they're a spectacularly good tool, but it seems like there's just a kit of maybe what a a five to a dozen very commonly prescribed ones. Why aren't people developing better, newer, new generation antibiotics? Seems like it would be a if for no other reason, a trillion dollar industry, but also save a lot of lives. I don't know whether there's a business reason for that or it's but it is an underfunded area like it's it's not where medicine has has turned enough attention and I I do think it's a genuine risk. All right. Well, some entrepreneurial young uh guy or gal or both will will launch into it. Um I want to understand the relationship between the immune system and cancer. But perhaps first we should talk about cancer, what it is and what it isn't. I think there's a lot of misunderstanding out there. um that cancer did not exist in uh our notsodistant past. I mean you hear this like people say oh you know cancer is a new thing because of the advent of you know all these devices with EMFs and radiation. That's certainly not what I believe. Has cancer been around a very very long time. Do we have evidence for that? Yeah. Yeah. I mean if anyone's really interested I I would highly recommend this book the emperor of all maladies which is a which is really a biography of cancer as a disease and talk about I mean the long history of going back as far as there's records of tumors of various kinds and and the misery associated with that we have a very different understanding of of cancer right now right and I think cancer is one of the most sophisticated where we have one of the most sophisticated genetic understandings of disease doesn't mean we can always do things about it but now we can understand mutations that accumulate in in cells and all of a sudden so the DNA inside of a healthy cell is there programming so if you have a skin cell your DNA is programming your skin cell to be a a skin cell in cancer all of a sudden some combination of mutations emerge in that cell that lose its normal regulation it the skin cell is no longer getting the proper signals from its DNA to stay in the right place and it goes and switches into a mode where it's dividing out of control and the result is that those cells will then transform into cancer cells. They'll start dividing. They'll lose the normal architecture. The risk is that they can disrupt things in the in the tissue where they are or that further mutations can accumulate and they can actually start spreading into distant sites in the body and that's metastasis. When you when you're when a cancer goes from one local site to another part of the body and as that happens it the those cancerous cells it's it's really an evolutionary process where those cancerous cells have acquired new genetics that are focused on their well-being. Those cells are dividing. They're growing out of control and they're taking the resources. They're they're they're growing at the expense of the normal coordination of the human body. And and that's that's really at at its core what what cancer is. It's genetic disease where cells lose the normal pro uh regulation and are dividing out of control in various tissues. I can see the picture in my mind where a otherwise healthy cell gets a mutation. We can talk about how mutations arise but and then starts uh spitting off daughter cells as it's referred to. Yep. Why would the daughter cells inherit the mutation necessarily to then create more cells because that's the prol proliferation of the tumor? Yeah, certainly cells propagate their DNA into their daughter cells. But um I could imagine a situation where every day some of our cells get a mutation, spit off a couple daughter cells, and then those daughter cells are are terminal as we say, right? And they don't create more cells. Is that happening all over the body every day? So does this so how is it that a the DNA that creates the further propagation gets passed from one one cell to the next? I do think this is happening constantly. It's a process that every time a cell is around especially as it's dividing there is some imperfection in how the DNA the DNA has inside each of our cells if that cell is going to replicate the DNA has to replicate itself. So you end up with two copies of DNA that should be the same. Each one being passed on to the two daughter cells of that dividing cell. That process of DNA replication is imperfect. And if there's any kind of damage during that process, one of those two copies might end up different than the other one, in which case you end up with a mutation now in one daughter cell and not the other. If that is dilitterious or if it's damaging, which probably most mutations are, those cells might start to die off. Okay. Something got the DNA got messed up. Those cells that are carrying that DNA die. Yeah. They can't take up glucose. They can't they just can't do cell stuff. And there's a lot of control mechanisms in the cell that say something something's wrong. Let's send a a programmed cell death signal to that cell. And cells will kind of implode with with various processes when something's wrong. And that that happens most of the time. The problem is if if if that change all of a sudden starts to not be damaging but to actually be a signal. Okay, now the cell is is growing more. It has some benefit that it's accumulated as a result of that mutation. Now that cell will start to divide more and that that cell that's carrying that first mutation might start dividing more. It both of its daughters now will pass on this this mutation that's made it divide more. And if in subsequent rounds it gets a second hit, it that the combination may go from just cells that are dividing a little bit more to cells that take off and become full-blown cancer. Now, there's certain processes that will accelerate that. One was exposure to things that cause DNA damage, right? The major one is is smoking. When smoking causes chemicals to go into your lungs, the the lung cells get exposed to these chemicals that then cause higher amounts of DNA damage, more mutations, and just as you have more mutations at a higher frequency, you're more likely to accumulate the set a set of mutations that will gradually go on to cause the generation of cancer. Another way that is that this process can be accelerated is that some people carry an underlying genetic predisposition to cancer. So people you will likely have heard of the brocha or the BRCA genes which predispose to breast cancer and other types of cancer. There people start with one copy that's already setting them on a road to higher risk of mutations accumulating and the whole process on in happens with a higher frequency and so this this march towards cancer cells is more likely to occur in people with that type of predisposition. How common is the BA mutation? Uh is it equally distributed in men and women? Um yeah, what can you tell us? And should everyone get tested for BA? And there's a lot of questions here. I'll ask them again one by one. Um and then of course we'll talk about things that could be protective, not just but certainly avoiding smoking would be paramount. So how common is breath? Yeah. So in terms of mut mutagens like the big ones are smoking sun exposure for melanoma. You know I know the balancing features of sun exposure but yeah we can talk about that but but clearly UV is is a risk factor for DNA damage in the skin. I mean I'm perfectly happy going on record. My the things I've said around in sunlight have been contorted so many different ways. It's like a pretzel twist now. No it's more like one of those balloon animals at a party but it's not it's a mess. The too much UV is bad for for skin cells. It's just bad. You need some, but too much is bad. Long wavelength light is great uh for and therein lies the challenge. But yeah, love sunlight, but you don't want excessive UV. Don't get avoid getting sunburned, folks. Yeah, thank you. So, yeah, the BA mutation. And I have a personal relationship to this cuz I lost both my graduate adviser and my post-docctoral adviser to bracka mutation related cancers 50 and you know just a little bit older than 60 and the other and you know brutal um especially when you you know one of them I know they're kids and you know it's um just for young people getting cancer and I know they're childhood cancers but ba seems pretty common. I don't know the numbers off the top of my head. I mean they're not the major like numerical causes of of of cancer in the scheme of cancers that developed. It's it's it's a it's a minority. It's a relatively small set number of the full set of cancers. The problem is if you inherit a broco mutation as an individual you have a very high risk of developing cancer. So it as an individual your risk goes way way up and of certain types of cancer in particular and we can all get tested for it now pretty cheaply right. Yes. Yeah. That's certainly recommended if there's a family history of of cancer for broa mutations and a a couple of other ones. But you're right it's the tests are available. And you asked about men and women. Mhm. It actually was was men were were some of the ways that those broco genes were identified because it's so rare for men to develop breast cancer. The ones who did develop it there was a thought well maybe there's an underlying genetic predisposition and that helped identify those genes. Interesting. Um everyone get tested for broa if you know because there are lifestyle factors that can reduce your cancer risk. I'd like to talk about mutagens. Yeah. Um, smoking bad. I'll go on record saying vaping bad. Perhaps not as bad as smoking, but still way way worse than not vaping. Uh, the battle to sort of protect vaping is is like beyond me. But, um, okay. Uh, to each their own. Um, environmental sort of and workplace hazards, you know, like known mutagens. If you work in a laboratory, you're working with mutagens, right? You're working with things that literally pull DNA apart. Yes. This always worried me working in a laboratory. There are a lot of carcinogenic chemicals in a laboratory for good reason. Yeah. This is the Yeah, we're we're trying to study cancer, but we're certainly working around a lot of things that could cause cancer, chemicals, radiation. Uh yeah, I don't know if you about you. I did a lot of lot of experiments radio lababeling cells. Yeah. I mean we well fortunately we worked with uh you know radiotagged amino acids with radiation that was we were told and I do believe was not not as as dangerous as some of the others but yeah I mean so chemical exposures are a big one. Yep. And so those those labels on paints and thinners and stuff in the garage that's real that's a real thing. They mutate cells and there's a you know there's some spectrum of stronger and less strong ones. And I think oftenimes we're operating in an absence of great data, but I you know I think there's a lot of things are implicated as potential mutagens, pesticides. Yeah, I you look at cancer rates in in um rural areas near where you know crops are dusted with pesticides and we've had Shauna Swan came on here and she's like listen you know the the cancer risks the you know endocrine disruptor risks we think of as like big cities as as dirty and dangerous and they are for certain reasons but she said if you really see the spikes in uh in these cancers uh related to environmental factors it's less so bus exhaust than it is pesticides. I mean, it is not evenly or fairly distributed. Some people get exposed way more to these things and we haven't studied them enough. We we need way more study to really be able to answer. Okay. And and and people shouldn't be left, this is my just me just speaking as it's kind of amazing to me how much we're left on our own to be figuring out what the risk of individual products is. And I I think it's a place where we should be investing a lot more to get clarity on where the real risks are. As many of you know, I've been taking AG1 for nearly 15 years now. I discovered it way back in 2012, long before I ever had a podcast, and I've been taking it every day since. The reason I started taking it, and the reason I still take it, is because AG1 is, to my knowledge, the highest quality and most comprehensive of the foundational nutritional supplements on the market. It combines vitamins, minerals, prebiotics, probiotics, and adaptogens into a single scoop that's easy to drink, and it tastes great. It's designed to support things like gut health, immune health, and overall energy. And it does so by helping to fill any gaps you might have in your daily nutrition. Now, of course, everyone should strive to eat nutritious whole foods. I certainly do that every day. But I'm often asked, if you could take just one supplement, what would that supplement be? And my answer is always AG1 because it has just been oh so critical to supporting all aspects of my physical health, mental health, and performance. I know this from my own experience with AG1 and I continually hear this from other people who use AG1 daily. If you would like to try AG1, you can go to drink AG1.com/huberman to get a special offer. For a limited time, AG1 is giving away six free travel packs of AG1 and a bottle of vitamin D3 K2 with your subscription. Again, that's drinkagg with the numeral1.com/huberman to get six free travel packs and a bottle of vitamin D3 K2 with your subscription. I get X-rays at the dentist now and again, but I prefer not to get them. X-rays cause mutations. Yeah. Again, there's a tradeoff and the dose and I, you know, when you need an X-ray, you need an X-ray, but I wouldn't do them for fun, right? Um I mean I have colleagues who prefer to do the slower um manual pat down at the airport um to going through the scanner. It's a low level of radiation is what they tell me. But if you're traveling a lot, you're getting multiple low-level exposures. And we know pilots, and this is for other reasons because they're, you know, you can tell us, but atmospherically they're exposed to more radiation. Cancer rates are higher in pilots. Now they're sitting a lot too. Prostate kids. Okay. There's a bunch of things there, but um do you yourself avoid the scanner at the airport? Honestly, I I do, but I can't say that there's data for that. I I feel the same way as you. Like if I could avoid it, I I try to minimize, but I that's not based on some inside knowledge I have, but I have the same bias of less seems better. Yeah. I mean, I'm not out to get the the scanner industry. Yeah, just I think it's useful for people to hear that that you could that one can have no formal data but an understanding of mechanism that leads them to to hedge. it's good to know. Are there any um mutagens and well is a carcinogen and a mutagen the same thing? So they're they're closely related. Mutagen I think means that you're mutating that you're changing the DNA in the cell. That's that's the idea that it's those mutations may or may not be linked to to cancer, but by virtue of the fact that you're causing more mutations, almost inevitably you're also increasing the risk of cancer and carcinogens are things that increase the ris rate of cancer. I love barbecued meat. I don't like barbecue sauce because it's sweet, but I I like meat with a char. Yeah. Yeah. Is the char bad? I think so. I mean, I like it, too, but Yeah. Yeah. Again, these are balancing decisions in life. Sure. But yes, there there there's some there is I mean meat in general has been implicated as a potential carcinogen, especially in colorectile cancer. There's some data around that. Mhm. Yeah. My read of those data, not the char data, but the the me data is it's tricky. Um from my this is just my standpoint. And I want to make sure I'm I put you know brackets around this that this is my read of the literature is that many of the studies that looked at meat rich red meat rich diets versus uh plant-based diets. The problem is a lot times the red meatenrich diets had a bunch of other things in them like sourcing wasn't considered. There was also a lot of um starches like because nowadays you find people who seem to at least feel better. Who knows about the longevity aspect, but feel better eating red meat, fruits, and vegetables, limited amounts of starches versus so I feel like the nutrition studies are a mess. They're kind of a disaster. I I certainly don't have clarity on that. Yeah. Yeah. And they and it seems like it changes the the the direction. I think some things we have pretty good common sense intuition about fiber. Yeah. ultrarocessed foods are probably bad like you know but I I think the balance of exactly what whole foods we're eating probably still needs to be worked out. How do you think about the data um on like for instance food dyes this is very timely um where a certain food dye yeah at a very very very high concentration in laboratory animals creates a significantly higher incidence of of tumors and cancers in those animals. But then the amount of food dye that's in the human food is is is a tiny fraction of that. Um I'm not trying to get political here. I just think as a framework for people to think about there are many carcinogens I'm sure right in this environment. I don't doubt that the lacquer on this table in fact if that's even what they used um uh if ingested could cause um could cause cancer. I don't I don't doubt that. Right. But I don't know that in its in its form here being near it uh for many hours a day does that. I I doubt it. We're not inhaling the table. This is what I mean by this this this level of confusion. I think we all live with this background confusion of things some study has been published in in mice at whole high concentrations exposure does mean anything in our lives. What's the relative risk? So that's why I start with smoking sunlight and then say there's a tail. And I I don't think we know fully what that distribution is yet. I'm sure there are some combination of things that are increasing our risk of cancer. We don't really know how to weigh uh duration and amount of exposure. And this is why I think it's really scary to people. People don't know, you know, they know smokers who don't get lung cancer and non-smokers who do and non-smokers who do. And so I think people go well like what they it actually has caused I I believe a lot of um damage in the faith in in medicine unfortunately because the messaging is all uh is mixed up. Yeah. I think that nowadays people are trying to do what they can to protect themselves, but people still get cancer. You can do everything right and still get cancer. Is that even if you don't have a bracket mutation? Absolutely. I mean, absolutely. You know, I think the last thing you ever want to do is like attribute someone's actions to to cancer. I mean, it is it is a probabilistic disease where some set of mutations occur that cause a really devastating disease. And so I yeah I mean I we don't know the answers and I think we have to be humble about that. Now what I I think we can also talk about is well like how how do we handle how do we treat cancer when it comes up and this is where these two conversations that we've been having really come together of when talking about the immune system. We went through a lot of I think I mean actually we went through a lot of sort of detailed mechanism thinking about the different cell constituents of our immune system. I will tell you that when I went to medical school, which wasn't that long ago, I graduated in 2010, the dogma was don't waste time thinking about cancer immunology. Cancer immunology is a field that's going nowhere. I mean, I think I I I was in Boston. I think that was a maybe there was some local bias in that direction, but this was not the mainstream of thinking about how we would treat cancer at that point. that the way the cancer was being treated was chemotherapy, which you know is something that's been around for decades. And it's basically give toxins to the body that will be more toxic to the cancer cells than to the healthy cells. And ask people to endure all the side effects because they have to to get rid of the cancer cells. And that's still the mainstay of of of cancer treatment. We all want to do better than that. It's very unpleasant. Very very unpleasant. Unpleasant and and worse. I mean I mean people endure hor you know it's it's we put put we put people through horrific things because it's the best we can do and then there was a wave of thinking okay well let's try to make drugs that are targeted to the mutations that we talked about and that was that was the hot thing that was the promising avenue when I was in medical school of like okay now we we've really measured that these are mutations that accumulate inside of cancer cells this is what's causing cancer let's let's make drugs that go after those things And turned out that that was although a lot of good has come from that people have extended lives, cancer has a way of working around that. And so these are cell cycle inhibitors. So signaling thing various mutations affect this these growth properties of of cells and there's targeted drugs that have been designed to go after some of those pathways that are making the cells divide out of control. Yeah, I think that benefit has come but cancer has ways of mutating around that and become developing resistance. The same way we talked about resistance in bacteria to antibiotics if they're exposed you can cancer cells are can evolve quickly and can become resistant to these targeted modifications. What has emerged as a whole new way of thinking about going after cancer is using the power of the immune system that we talked about at the beginning and redirecting that against cancer targets. This has changed how we think about cancer treatment. It's the hope is that all of we tal we we talked all of us have this immune system that goes through every organ in our body. It circulates. We have white blood cells that are constantly going around and looking for things that shouldn't be Can we unleash that immune system against cancer? And the hope would be that the cells that our immune system, we've talked about how they're really exquisitly evolved to make a determination of this is a healthy cell, this is not a healthy cell, this this cell should be here, this should not. If we could get that level of precision where we could have a durable immune response that gets rid of the cancer cells but leaves the healthy cells intact, that is what we want. Mhm. Now that is not science fiction and has is is now approved and used to treat a number of different cancers. The first place where this happened was in a class of medicines called checkpoint inhibitors. Um or amunotherapy drugs uh a lot of a lot of people will have heard of these things. PD1, CTLA4 are some targets where there are drugs that get infused that hit these things that are on the surface of TE-C cells and they actually are natural breaks to the TE- cells. Te-E cells might be in our body there but turned off or not turned on enough to be strong enough against cancer. And for certain types of cancer, it's been absolutely miraculous that if you make a drug that hits the break on the on the tea cells, the tea cells go stronger and they can be unleashed against cancer just by taking the brakes off of them. What sorts of cancers has it been successful for? The poster child for this has been melanoma. Mhm. One of the big success cases was was Jimmy Carter who had a melanoma which is a skin cell aggressive skin cancer that had already gone to his brain which was thought of as a death sentence and he got treated with checkpoint inhibitors and basically was cured. Amazing. Um and so you know they saw these tumors just shrink away and in and not just him but in a in a large fraction of of melanoma patients now respond to these. And so that that has changed how melanoma is treated. It's and other cancers to varying degrees because some types of cancers can respond to this. That's taking the a drug that unleashes the tea cells that are already in our body. The focus of my research in is well the first thing I said was we're living in this amazing moment of biology where we can we can do things to cells in our body that with incredible precision and and we're often just limited by our imagination. And what we can see now is that we don't actually have to just be limited to the cells that the tea cells that are natural in our body that already have this random distribution of sensors. We can actually genetically make a a one of these sensors for tea cells and put it into te- cells. We can put in put a gene that encodes something on the surface of tea cells that will make them programmed to search and destroy for cancer cells. Now, this is this is largely known as chimeriic antigen receptor tea cells. That's a long term. They're known for short as CART cells, chimeriic antigen receptor. And what that means chimeic is that these are stitched together. This is a receptor that was designed in a lab, does not exist in nature, but can be put into a piece of DNA, delivered into a TE-C cell, and when that DNA goes into the genetic code of the T- cell, all of a sudden the T- cell will start making proteins that go on its surface and act as these artificial sensors. And those cars then when those tea cells get reinfused into a patient the way that you get like a a blood transfusion those cars are directed to go against cancers. This has been done for certain types of leukemia and lymphoma. And there's been these amazing success stories. The thing that woke up me and the world was in 2012 there was a young girl who was the first pediatric patient to be treated with a cartis cell for for cancer. So she she's become a heroic figure uh Emily Whitehead. She was I think eight at the time and she had a form of leukemia that hadn't resp it just was for some reason whatever reason it failed all the treatments and it just nothing worked. She was going to be sent home on hospice. She had exhausted all the possibilities at the age of eight and she got enrolled in a at that time highly experimental treatment to get these CAT tea cells. So her blood cells were taken out in a big blood donation. her own tea cells were genetically modified and we could talk about how that was done. It's actually done with like a pretty crude technique that's been around actually used viruses, lentiviruses. These are sort of modified HIV viruses to deliver this extra piece of DNA that encoded the car. And this was done on her cells. And then after that extra gene was put into the tea cells, the tea cells were reinfused into her body. And it was not a straightforward course. She she ended up in the ICU. The immune system had to we people in real time people had to figure out how to control the immune systems and the side effects. But as that was controlled, all of a sudden the her cancer cells disappeared. Amazing. And the lentivirus itself didn't uh didn't spark a an immune reaction that was that outweighed the benefits of of the cargo. No, amazingly it really hasn't. I mean there there's been some discussion about the risks of using these lentiviruses and we we'll talk in a second about how we can do better now. Yeah. People are going to hear uh putting viruses into cells and putting them into humans and a bunch of people will freak out. But I I promise you that things like adeno, which is like a cold virus, or lenti, which is similar to HIV. And of course, they didn't give her HIV. They changed the virus, so they're not delivering HIV. These viruses are incredible because they can create longlasting expression of genes that you deliberately put into them. They're a shuttle. It's an amazing application of biological understanding, right? that all of a sudden we've been studying viruses because of the risk that they have, but we've learned that they can deliver that that viruses have evolved to be very good shuttles and to deliver their genetic material into cells. The way I think of it uh that is the viruses have evolved to take advantage of our biology and our genes. And so we did the ultimate touch in these instances like you're so good at at hijacking our cell's DNA and proliferating. All right, we'll leverage you to help us as opposed to hurt us. Right. That's exactly right. And so that was done in 2012. Emily Whitehead was eight. It was done as an experimental treatment at the University of Pennsylvania. And the story now is that now all these years later, Emily White is not only cured of her leukemia, she's premed at the University of Pennsylvania. So awesome. And so no one could ignore that. You know, this was this wasn't this was just all of a sudden this dogma that I had just been taught a couple of years early in medical school that we should ignore cancer amunotherapy. It was just we were just wrong. And all of a sudden the field woke up and said, "Okay, the immune system is not just limited to treating viruses and bacting us from viruses and bacteria. The immune system can be exploited and potentially re-engineered to protect us from cancer and maybe other diseases." So that was 2012. 2012 also was the year that a paper got published in science by Emanuel Sharpantier and Jennifer Dana that introduced this new technology called crisper and we can we'll talk about this but fundamentally is a tool to rewrite DNA sequences that came out in 2012 and on a personal level 2012 was also the year that I moved to San Francisco to start a lab studying tea cells and how genetics influences te- cells. I was looking around and trying to figure out what my lab would do and all of a sudden I was arriving with a empty lab space at exactly the same moment that that the world was shown that te- cells could cure cancer and that we had a tool that could potentially rewrite DNA sequences and that we wouldn't be limited to these lentiviruses which are kind of clunky the best tools we had at the time but pretty clunky and non-precise in how they insert genetic material. All of a sudden, we could imagine that we could take tea cells and use crisper to actually pick individual places in the genome and make targeted changes to program exactly how cells behave. And that is the basis for my ongoing work. We've put a lot of work over the years into being able to now take crisper technology, get it to work in TE-C cells to learn the rules about what are the genetic changes that will be most effective at making TE- cells into into amunotherapies that cure patients for with different diseases and then to go all the way and then actually use crisper to make tea cells that can be input into patients with new levels of precision and power and that's that's in clinical trials now. We're now in clinical trials with these crisper engineered CARTT cells and we're not just going after leukemias where these CARTT cells have historically worked but we're also thinking about can we make these work for the really common causes of cancer deaths solid tumors and that's been a challenge and we can talk about that but getting tea cells to find the right targets in tumors and then work inside of tumor environments which are inherently imunosuppressive requires figuring out additional gene edits that are now possible with crisper to try to beat the cancer at its own game. If cancer is evolving to to make itself cloaked from the immune system, now with crisper, we can think about getting one step ahead and making tea cells that are able to be resist all the tricks that cancers throw at it to be more and the I think we're on the brink of having precise crisper engineered cells that will I I hope start to melt away cancers without the side effects of chemotherapy. Amazing. Uh just amazing. And the story of this young woman is spectacular. Um, I have two questions before we talk about crisper technology. The first one is, is it true, I believe it is, but is it true that cancer risk goes up as we get older? And if so, why? Um, so that's the first question. And then uh the other question has to do with how the the amunotherapy that you described um was able to target the cancer and and not cause problems elsewhere which is kind of the major issue of chemo and radiation therapy. But the first question um again was you know why more um mutations as we get older. So I think there's there's a few cancers that that peak in childhood and there's risk as as the body's developing of certain cancer childhood cancers and there's childhood leukemas for example then that like when we talk about Emily Whitehead but most cancers as you said exactly as you said that there's this sort of increase and they're largely disease of later stages of life. I think that the reason for that is remember when we talked about what causes cancer it's this evolution where c cells start to accumulate mutations numerically a lot of the cells that have the mutations will die off and it's just a game that unfolds over time and the more time you have cells dividing and sticking around in the body they're accumulating more damage and eventually you're more likely that that damage would actually transform the cells into a cancer cell. So time is is is is a big factor here. time and just accumulated damage. And the other question was, you know, how is it that the lentivirus knows to um the lentiviral uh cargo carrying tea cells uh know to attack the cancer and not something else. So this is a key question for the field, right? And I think one of the things that worked incredibly well was a brilliant choice by a group of scientists in different a few different places that converged on the target that was used in the first CARTT cell. And what the target is known as as is is a protein called CD19. That's just the name of this thing that's found on a lot of different types of B cells. So this brings us back to this discussion. the the leukemas themselves are a disease, a cancer of the immune cells. So they're cancer of B cells and CD19 is is found on the on the surface of many a large number of different types of B cell leukemas and lymphas. I see. I think one of the things that turns out to be serendipitous here is that B cells themselves natural healthy B cells actually also have CD19 on their surface. What just turns out to be serendipitous is that the body can tolerate those cells going away. And so what has made this a particularly effective and safe and relatively well tolerated treatment for cancer is that the collateral damage is actually not that damaging. That te- cells in this case are not strictly distinguishing between cancer and health. They're not just getting the leukemia cells. They're they are getting collateral B cells. But by and large to a first approximation, people can live without those cells. And so that side effect has just been tolerable. Finding that balance gets harder and harder for more cancers. Right? If you start to think about pancreatic cancer or brain cancer, finding targets that if you hit the healthy pancreas or the healthy brain are not toxic, it's it's harder and harder. So people are thinking about more and more sophisticated ways to look for these targets that are selectively found on the cancer cell and not on the healthy cell or to think about ways that you might actually make the cell depend on recognizing multiple features so that you can have what's sometimes talked about as like a two-factor authentication like the T- cell will only kill cancer if it finds this and this and that combination of things are not found on healthy cells even if one or the other might be. So people are thinking about how do we get more sophisticated about building these discrimination systems into tea cells. The building blocks are there but the specifics for each cancer have to be invented but but we have the tools to do that. Awesome. Before we talk about crisper there was one other question that I know many people will be thinking about. Uh a few years back, maybe five, ten years back, there was a a lot of discussion, maybe even some enthusiasm about ketogenic diets to treat or prevent cancer. And my understanding from looking at that literature was that for some cancers it perhaps, I want to bold uh underline and and capitalize perhaps um might help, but for other cancers it could make things worse. And then uh I also more recently started hearing about uh low glutamine diets. Um so and of course this is the way the internet works but um but I did see some papers in some decent journals you know uh that at least we're exploring this. So are um low they're just low carb let's call it what they are ketogenic diets um have they been shown to be useful for treatment or avoidance of cancer? I have to defer to you. I actually I don't I don't know the answer to that. Okay. My my guess is that um people are still looking at this, but you know there was also the idea that they could be useful for um certain forms of dementia. There was an effort to call dementia, you know, type three diabetes, but my understanding from talking to the experts in this is that um it might help through indirect mechanisms, but that it's not going to solve the problem. Um okay. Well, thanks for entertaining that little uh culde-sac that I created. Crisper, tell us the story of Crisper. Uh because I think crisper is one of those funny things in biology and medicine that almost everybody has heard about in the general population. Most people know it has something to do with changing genes, but it's sort of like AI. it's here. Uh it's powerful. It scares certain people. It excites other people. Um but most people don't know how it works because there's really no incentive to. But I think the story of Crisper is actually also a story about uh how science works and that's important too. I think it's exactly true. I think it is a perfect illustration of something where a discovery happened that no one was planning but changed biology. Um let me tell this story in two separate arcs. One arc is the arc of understanding DNA. You know, if you go back to Watson and Crick, it's understanding the double helix to understand the structure of the DN what a DNA sequence is that mature as we learn how to sequence to understand the to be able to measure a row of ATS and C's and G's that in whatever combination they are will start to be the building blocks for programming which proteins get made inside a cell. And then around 2000, we get to the first draft of the human genome, which is this multi-billion dollar project across the world to come up with a draft of one human genome sequence milestone for for biology and medicine. And then DNA sequencing technologies continue to improve and cost comes down. We're getting to the point where we can start to measure big chunks of our DNA at increasingly affordable costs. And people were starting to understand the differences between people with DNA at the level of at least statistics. Okay, people with this disease are more likely to have this this gene than that. But we're getting to some limit of what we can do just by sequencing DNA. All of a sudden, you you're observing the DNA sequence that's in someone's cells, but you don't really know what those effects are. Just as the sequencing world is is maturing, we're desperately looking for a tool to say, well, now we want to as we have all the sequences, we want to be able to see what happens if you change a sequence. And people were stumbling around looking different tools. There were there were there was a range of these things. There were zinc fingers. that people lentivirus was another one that we just talked about that with different degrees of efficiency and people were trying to to be able to change DNA sequences and cells and it had been a long-standing effort. Out of nowhere emerges crisper as the answer to this problem. crisper was being studied as an an interesting and unusual set of DNA sequences that were found in certain types of bacteria. There were these repeated sequences and no one knew what they were. And people out of real basic curiosity about what was happening in bacteria started studying these repeat sequences and what they were doing. And little by little by little it was worked out that these repeat repeat sequences actually ba formed the basis of a kind of immune system for bacteria. Now we talked about the human immune system. Bacteria are just an individual cell but they're also susceptible to infections which is a sort of a strange idea. Bacteria cause infections in us but there's this arms race between organisms. Everyone's trying to kill everyone else. And so bacteria are constantly being bombarded by certain types of viruses. They're called bacteria phagee viruses and they've evolved a series of bacteria have evolved a series of defense mechanisms to protect themselves from from these viruses. Crisper turns out to be a bacterial defense mechanism against viruses which is kind of amazing that this that this thing that has entered into popular culture is a bacteria protection against bacteria phage. Now why has this caught the world of biology by storm? Well, what was realized was that the way that that crisper works to protect against itself um the protect bacteria from viruses is that it can recognize particular sequences of DNA which are virus sequences and discern discriminate whether it's a virus sequence or its own bacteria sequence and it actually does that by scanning across the DNA and finding something that's recognized as a virus target and not a bacteria target. And when it finds it, it makes a cut. Okay, now this sounds technical obscure, but what was recognized and this became the basis for a Nobel Prize of of with Jennifer Dow and Emanuel Sharpentier. Many people around the world have contributed to this field. Um what was realized was that this could be repurposed as a tool. If we take it out of bacteria, we could actually exploit this with this crisper system that had evolved to protect bacteria. And the same rules that allowed bacteria to to scan across DNA and find a virus sequence and cut it could be used to scan across any DNA and cut at a particular sequence. That's the power of crisper. Now, why do we care so much about being able to cut a particular sequence? If you can cut, you can also start pasting. You can cut out genes that are limiting the that you don't you don't want to be in a cell. You can start pasting in sequences to replace mutations that cause disease. We can start pasting in big sequences like the sequence for cars or other types of things that will make TE- cells more powerful. So, and this is I'm I'm focused on TE-C cells, but this is in now in every aspect of biology. People are studying this in plants and to make crops that will be drought resistant. People are studying this in in in every organ system to understand every type of disease and to build new new types of molecular medicines. There's one other feature of crisper that's that's really important in this story. It's not just that this crisper can cut at a specific sequence that it's evolved to cut at virus sequence. It's the way that it cuts that has made it really catch on in a way that none of these earlier technologies do. So crisper, if you think of it as a it's an enzyme that can cut DNA and it it can cut essentially almost any sequence of DNA. So how does it decide which sequence to cut? It does it by actually pairing with an RNA molecule. So crisper sometimes called cast 9 which is a particular type of crisper system um is a is a combination of a protein which is a scissor and then an RNA that sticks to it and the RNA is what actually programs where that scissor will cut. Okay. So this and and what's so special about that is that we actually know with perfect nearperfect precision the rules of how an RNA will recognize any DNA sequence. There's a complimentarity where you you can match up and know exactly which RNA you want to design. So you can now cut DNA sequences at will. And it's gotten to the point where now if we want to cut a piece of DNA, we order a piece of RNA off the internet. It shows up in in in the lab in a matter of days. We mix it with cast 9 protein and then that's going in tea cells the next day and we're able to introduce a cut into any DNA sequence. So now you go back to the genome sequence that was came out in 2010 and all of a sudden you can go on the internet, pick a place in the genome that you're interested in studying, order a piece of RNA, make your your targeted crisper molecule and make a cut or a cut and a paste at that particular site and then in a very tangible way read out the consequences. you're going into the source code of DNA inside of a cell and you can when you make that change you can say what what happens to the cell. Does it is is it a stronger response? Is it a different response? We can test it in test tubes. We can test it in models of disease and then as we learn the rules we can actually take those crisper modified cells all the way and infuse them into patients. Incredible. and thank you for that incredibly clear and detailed um explanation of the crisper cast 9 system. A couple of questions. How precise is the cut? Are you damaging adjacent nucleotides or can you home in exactly on the site that you want to cut? And then if the related question is if you're going to introduce a gene sequence there um how do you ensure that there aren't downstream effects? I mean, I think what you're getting at with both these questions are unintended consequences and that's always present, right? I think this has been a major concerted effort for the field of crisper. How do you get more and more precise and it's come a long way, but nothing's perfect, right? So, I think we've done a lot the field has done a lot of work to test offtargets, right? If you're programming to cut on one place on chromosome 6, do you actually evidently accidentally ever cut anywhere else? And there's a range. Sometimes some sequences are a little bit more promiscuous than others. But we've gotten quite good at getting more and more precise to say, okay, we're making these high fidelity cuts that at at one place. There are still the second risks of bystander effects. Okay, you make a cut. What does the DNA get chewed back? And at the neighboring part, there's been in some extreme places pieces of chromosomes actually falling off. I all these things can happen. And I think what we're kind of at a place in a field where now we're thinking about for each disease a risk benefit of okay, there's going to be there's always a risk for any medicine of some unintended consequences. We have to be on the lookout for them. We have to know what what they are. Most cells, as we said, that get a mutation don't have a problem. They just die off. So if you have an unintended consequence, most will die. But there is always the risk of the unintended consequences. And I think as a field, we have to be humble about that. That said, the the the crisper world is not static. And what I what I the story I told you was like the building block of crisper. It's a protein scissor that can be targeted to any piece of DNA with an RNA molecule. people are appropriately thinking well scissors can cause damage. Maybe that that crisper molecule should actually be re-engineered not to be a scissor but to do other things. And now people have started engineering it to say well let's not make it a scissor. Let's make it a thing that just introduces a more predictable mutation at a site. David Louu at Harvard has created these things called crisper base editors that doesn't introduce a doublestranded break but actually changes nucleotides in a more predictable way at that site by recruiting a damnase domain something that will change DNA nucleotides when it's recruited to a particular place and you use crisper just to recruit that enzyme that makes that mutation at a targeted place other people have actually started using epigenetic enzymes that DNA doesn't just get enacted by DNA sequences but can actually pieces of it can be active or inactive and this is called epigenetics where there can be a stable program of things getting turned on or off without any change in the A's and T's and C's and G's and now we and other others are using crisperbased epigenetic editing it's called epiediting where we don't make any cut in the genome but we just turn on or off and it's in a large part to think about mitigating some of these risk risks that might come with the scissor function. Instead, all of a sudden, we're thinking about we're using the same building block of recruiting an enzyme to a particular place in the DNA code, but using the full set of things that we might do at that DNA site to program cells in the most precise possible way. I'd like to take a quick break and acknowledge one of our sponsors, Element. Element is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium, all in the correct ratios, but no sugar. Proper hydration is critical for brain and body function. Even a slight degree of dehydration can diminish your cognitive and physical performance. It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium, and potassium, are vital for the functioning of all cells in your body, especially your neurons or your nerve cells. Drinking Element makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. My days tend to start really fast, meaning I have to jump right into work or right into exercise. So, to make sure that I'm hydrated and I have sufficient electrolytes, when I first wake up in the morning, I drink 16 to 32 ounces of water with an element packet dissolved in it. I also drink Element dissolved in water during any kind of physical exercise that I'm doing, especially on hot days when I'm sweating a lot and losing water and electrolytes. Element has a bunch of great tasting flavors. In fact, I love them all. I love the watermelon, the raspberry, the citrus, and I really love the lemonade flavor. So, if you'd like to try Element, you can go to drinkelement.com/huberman to claim a free element sample pack with any purchase. Again, that's to claim a free sample pack. I'm curious about getting crisper into the cells of interest. Yeah, you know the lentivirus example that you gave before um my understanding is it involved harvesting some tea cells um introducing the lentivirus with the you with the cargo that you want putting that back into circulation and the tea cells know where to go and know what to do. uh for a lot of cell types like neurons in the brain, uh liver cells, pancreatic cells, um I could imagine a surgery where you inject directly into those organs, but uh wouldn't it be wonderful if you could um get the cells of interest from, you know, without having to be so invasive? Um so what's being done there in terms of trafficking um crisper 2 appropriate cell types or andor or organs and then that uh sort of seeds another question that I'll I'll hold off on about whether we should be banking uh cells or or uh for what's coming. First of all, I just want to pause for this this is this is great. I love this conversation. No, I do too. I mean, you're taking us to the the I don't like the phrase bleeding edge. sounds of violent, but you're taking us to the cutting edge of molecular biology and medicine and we are peering over into what's next like what your children and my children and are probably our parents also will uh be able to benefit from in the next 10 years maybe sooner. Yeah, we're really talking about things that are happening now and and happening at an accelerating rate. So you asked part of what just got made me have that reaction was I think you asked one of the key questions for this field of how is this being delivered into cells. So I told you let me go backwards and…

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