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Dr. Alex Marson on Huberman Lab: How CRISPR can cure cancer

Checkpoint inhibitors unblock T cell attacks, reversing melanoma; CRISPR now rewrites T cell DNA directly, extending targeted immunotherapy to solid tumors.

Dr. Alex MarsonguestAndrew Hubermanhost
Mar 9, 20262h 27mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 2:21

    Alex Marson

    1. AM

      We're living in this amazing moment of biology where we can put a gene that encodes something on the surface of T cells that will make them programmed to search and destroy for cancer cells.

    2. AH

      Mm-hmm.

    3. AM

      Now, this is largely known as CAR T cells, chimeric antigen receptor. This is a receptor that was designed in a lab, does not exist in nature. When those T cells get reinfused into a patient the way that you get, like, a, a blood transfusion, those CARs are directed to go against cancers.

    4. AH

      Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. [guitar music] I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford 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. 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

  2. 2:21 – 5:56

    Diseases & Current Biological Landscape; AI & Computational Tools

    1. AH

      Marson. Dr. Alex Marson, welcome.

    2. AM

      Andrew.

    3. AH

      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.

    4. AM

      Thank you for having me. Really, really good to see you.

    5. AH

      Yeah, it's been a while. Let's start off with the big picture.

    6. AM

      Yeah.

    7. AH

      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 gonna 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?

    8. AM

      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 in, at the root causes of disease. And over the course of this conversation, I imagine we're gonna 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 in 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 CRISPR, but it's also being done with lipid nanoparticles 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.

    9. AH

      Super exciting. Do you think that molecular biology and genetic engineering and/or AI are the reasons that things are on this accelerated timeline?

    10. AM

      Yes is the answer.

    11. AH

      Mm-hmm.

    12. AM

      All of those things.

    13. AH

      Mm-hmm.

    14. AM

      I think we can do experiments at a different level of scale. We can generate data, and then we have the computational tools, inc-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 at, 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 and reading out the consequences and directly being able to observe the effect. And w-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

  3. 5:56 – 10:55

    Immune System, Innate vs Adaptive Immune System

    1. AM

      disease.

    2. AH

      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 gonna form the kind of building blocks of our discussions about cancer and, and other things today.

    3. AM

      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 I- 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, at its core that's, that's the, the basic job of the immune system.

    4. AH

      To recognize us versus non-us.

    5. AM

      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 t- 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, it, that's foreign, that shouldn't be there.

    6. AH

      Mm-hmm.

    7. AM

      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 s- cells like dendritic cells, macrophages, 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 tri- 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. W- and the major players in the adaptive immune system are a group of white blood cells that are collectively known as lymphocytes, but we'll talk about B cells and T cells in particular, which are major groups of, of lymphocytes. We've been focused heavily on T cells. T cells play a central role in coordinating th- the fine-tuning of the immune response. One of the amazing things about the T cells is that each T 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 germline sequence. Each T 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 T 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 re- receptors that are, have developed on our T cells. Each one will have a different unique receptor on its surf-- 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 their ... When they're engaged, they send a signal to the T cell that, okay, y- we found something that, that you've been programmed to recognize and programmed as recognized as foreign if it, if the immune system is working properly.

    8. AH

      And are the genes, uh, that these T 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 germline.

    9. AM

      Yeah.

    10. AH

      But we should clarify the, the germline-

    11. AM

      Yeah

    12. AH

      ... is not about infectious germs in this context.

    13. AM

      Yeah. Yeah.

    14. AH

      The germline, uh, DNA is from the sperm and egg-

    15. AM

      Yeah

    16. AH

      ... that were your parents.

    17. AM

      Yeah.

    18. AH

      It became you. There's recombination of those genes, and then there's you all, um, each and all. Um, and the T 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?

    19. AM

      Largely random. Uh, th- it's actually there's the pieces of DNA at, at this part of the, the DNA actually recombine and get pasted together in, in unique ways. And-

    20. AH

      So it's probabilistic.

    21. AM

      It's probabilistic, and that's what allows us to have cells that lying there and 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 T cells lying there waiting that could be engaged by those proteins o- on the surfac- that viruses would introduce.

    22. AH

      That's

  4. 10:55 – 13:23

    Thymus, T Cell Selection; B Cells & Antibodies

    1. AH

      incredible. Would you mind mentioning the, the role of the thymus?

    2. AM

      Yeah.

    3. AH

      These days I'm hearing more and more about we have a thymus-

    4. AM

      Yeah

    5. AH

      ... then we lose a thymus.

    6. AM

      Yeah.

    7. AH

      Would it be beneficial if we could keep our thymus around?

    8. AM

      So thymus is, is actually the reason that T cells are called T 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.

    9. AH

      Mm-hmm.

    10. AM

      And it is the place where T 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 culled, they get selected, and they, the ones that by accident are generated that recognize something that isn't supposed to be in your body, if, 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.

    11. AH

      There's sort of a negative selection-

    12. AM

      There's a negative selection

    13. AH

      ... of the stuff that's you so that your immune system doesn't attack you, and it knows you from non-you.

    14. AM

      Yeah. That's exactly right. There's actually both a positive selection and a negative selection. That's exactly the right way to think of it.

    15. AH

      Mm-hmm.

    16. AM

      The cells getWill only emerge from the thymus that if they have a s- a, a, a receptor on their surface that's there, so th-th-that's a one s- positive selection. But if it engages with a self-target in the thymus, it gets negatively selected. So what comes out are T cells that are there with sensors in place to recognize things that shouldn't be there.

    17. AH

      Okay.

    18. AM

      Yeah. Yeah.

    19. AH

      So y-your thymus and your T cells get educated-

    20. AM

      Yeah

    21. AH

      ... in childhood.

    22. AM

      Yeah.

    23. AH

      And that's what you're working with, except that the immune system can adapt and make antibodies to things it doesn't recognize.

    24. AM

      The antibodies come from the, from the other f- type of lymphocelle, cell, lymphocytes. So now, now we can talk about the B cells. B cells are this other type of lymphocyte that work in coordination with T cells, and they're the antibody-producing cells. So they actually have a similar process where they're generating different antibodies at random w- through a similar kind of recombination event. They have their own form of selection that they go through.

    25. AH

      Mm-hmm.

    26. AM

      And then those antibodies can then be released into the bloodstream and, and are the basis for protection against infections after we

  5. 13:23 – 16:11

    Sponsors: BetterHelp & Helix Sleep

    1. AM

      get them.

    2. AH

      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, whether or not that's with work, with relationships, my personal life, or simply my relationship with myself. There's just so much benefit that comes through effective therapy, and that's not just my personal experience. There are loads and loads of clinical studies to support that. With BetterHelp, they make it very easy to find an expert therapist who can help provide the benefits that come through effective therapy. They have a short questionnaire to help match you to the ideal therapist for you. And while BetterHelp has an industry-leading match rate, if you aren't happy with your match, you can switch to a different therapist anytime. Also, because BetterHelp is done entirely online, it's extremely time efficient. You simply log on and have your session. If you would like to try BetterHelp, go to betterhelp.com/huberman to get 10% off your first month. Again, that's betterhelp.com/huberman. Today's episode is also brought to us by Helix Sleep. Helix Sleep makes mattresses and pillows that are customized to your unique sleep needs. Now, I've spoken many times before on this and on other podcasts about the fact that getting a great night's sleep is the foundation of mental health, physical health, and performance. When we aren't getting great sleep on a consistent basis, everything suffers. And when we are sleeping well and enough, our mental health, physical health, and performance in all endeavors improve markedly. Now, the mattress you sleep on makes a huge difference in the quality of sleep that you get each night. How soft it is or how firm it is all play into your comfort and need to be tailored to your unique sleep needs. If you go to the Helix website, you can take a brief two-minute quiz, and it will ask you questions such as, "Do you sleep on your back, your side, or your stomach?" Maybe you know, maybe you don't. "Do you tend to run hot or cold during the night?" Things of that sort. You answer those questions, and Helix will match you to the ideal mattress for you. For me, that turned out to be the Dusk, D-U-S-K, 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 helixsleep.com/huberman, take that two-minute 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 helixsleep.com/huberman to get up to 27%

  6. 16:11 – 20:56

    Immune System Health, Sleep, Diet; Genes

    1. AH

      off. What, um, [lip smack] 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-

    2. AM

      Yeah

    3. AH

      ... or our, uh, our immune system is impaired." Um, the one thing that I'm certain, uh, supports the immune system is great sleep.

    4. AM

      Yeah.

    5. AH

      Right? And we just know this. If we don't sleep well or enough, we get sick. Is that because there's a, a, a known impairment of the immune system?

    6. AM

      I, I wonder about this too. I mean, I agree. Anecdotally, I've experienced that so many times of being run down and then being, being, feeling, experiencing that I'm susceptible to infection. But I, I don't actually know the basis of that. I mean, th- 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 w-we're doing, where, you know, we're studying largely steady state, uh, uh, uh, uh, 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, uh, someone in my lab, a, a postdoc named Sagar 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 T cells. And this, th-there's some sub-growing stuff on this.

    7. AH

      Mm-hmm.

    8. AM

      But it's another, like, what, what are the determinants of it? He did an ex- he did experiments in my lab where he exposed some, an allergen, something that irritated the skin and caused an allergic type reaction in, in the skin of mice. He did it in mice that were eating a normal mouse diet versus a high, high-fat diet that caused obesity. And what we saw was that it was actually n-not just a quali- a quantitative difference in the immune system, but actually a qualitative difference.

    9. AH

      Mm-hmm.

    10. AM

      The actual type of inflammation, the cell responses were different in, in the mice eating a high-fat diet. And I think we haven't done enough studies like that, where we actually start playing with the variables of life-

    11. AH

      Mm-hmm

    12. AM

      ... and test them in, in a mechanistic way to isolate individual variants. What was interesting there was thatThe 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 diet mice would respond favorably to these. It, it, they didn't help the, the mice that had the obese high-fat diet respo- response to inflammation, and in some cases, it actually maybe made it worse.

    13. AH

      Interesting.

    14. AM

      So, so I think that there are these, these systemic ways, I mean, clearly we kn- 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.

    15. AH

      I realize I'm asking very top contour type questions for which there probably aren't specific answers, but, uh, we all know people that, um, get sick all the time. Um, and we know people who never seem to catch-

    16. AM

      Mm.

    17. AH

      -the bugs that everyone else-

    18. AM

      Yeah.

    19. AH

      -seems to catch. Is there any understanding of what a more robust immune system is at the level? Is it more T cells? Is it, um, but, you know, are the, the B cells engaged more quickly so they can generate antibodies more quickly? What is it?

    20. AM

      [chuckles] These are-

    21. AH

      You know?

    22. AM

      -great questions. I, I, that I don't think have full, full answers.

    23. AH

      Mm-hmm.

    24. AM

      There are, there's been a lot of work on gen- genetic determinants, 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.

    25. AH

      Mm-hmm.

    26. AM

      And you see that there are certain types of infections that either happen or happen with a, a different type of severity in people with genetic deficits in cer- 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 y- 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 multifactorial.

    27. AH

      Mm-hmm.

    28. AM

      And it's, it's, it, you know, it also becomes this interplay between the health and then what you get exposed to by, by

  7. 20:56 – 25:27

    Childhood Exposure & Allergy Prevention; Autoimmune Reactions

    1. AM

      your environment.

    2. AH

      Yeah. Speaking of which, uh, I'm familiar with some studies from Stanford, I believe, where, um, kids that have no exposure to peanuts get peanut allergies.

    3. AM

      Yeah.

    4. AH

      And, um, careful, subtle-

    5. AM

      Yeah.

    6. AH

      -increasing exposure to peanuts-

    7. AM

      Yeah

    8. AH

      ... essentially, um, protects them against peanut allergies. So i- is it true that when we're young, that exposure to pathogens, um, [chuckles] and different foods, uh, gives us a more robust immune system?

    9. AM

      I think that there's, that 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 par- particularly susceptible to becoming tolerant.

    10. AH

      Mm-hmm.

    11. AM

      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 hypersensitive 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 wanna expose kids who are gonna have a da- a, a, a dangerous allergic response. But on the other hand, critical early exposure is part of how tolerance is maintained, and I th- I think peanut allergies, there, there is strong evidence that exposure to peanuts can be beneficial p- in people who are not yet allergic.

    12. AH

      What's going on w- with autoimmune conditions?

    13. AM

      Yeah.

    14. AH

      Is this that the, the B cells and T cells are at a probabilistic level, the T cells developed, um, some reaction, so to speak, a, a binding to, um, cells that we naturally-

    15. AM

      Yeah

    16. AH

      ... make that they shouldn't have, that it's just like it happens?

    17. AM

      Yeah.

    18. AH

      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 ha- experienced that as a master's student. I, I was working so much-

    19. AM

      Mm

    20. AH

      ... and probably not eating enough-

    21. AM

      Yeah

    22. AH

      ... and drinking so much caffeine back then that I got some kind of funky skin lesion things. I went to the doctor and they're like, "Oh, you're starting to get some, uh, attack of the deeper layers of, of your skin. Um, you just need to work a little less." And sure enough-

    23. AM

      Right

    24. AH

      ... did that and-

    25. AM

      That did the trick?

    26. AH

      It did the trick. Uh, 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.

    27. AM

      Yeah.

    28. AH

      And it, it overshot the mark, basically.

    29. AM

      I sort of walked you through it 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, that 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, in practice, T cells escape from the thymus that do recognize our own self-antigens. And there's actually secondary mechanisms that sort to block that, but autoimmune diseases emerge when those normal checks fail.

    30. AH

      Mm-hmm.

  8. 25:27 – 30:51

    Whole Body Immune Response, Cytokines & Fever; Antibiotics

    1. AM

      by the immune system.

    2. AH

      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 h- like wh- 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 body-wide response-"

    3. AM

      Yeah

    4. AH

      ... as opposed to a localized response. I can i- I can imagine like with a splinter, of course-

    5. AM

      Yeah

    6. AH

      ... you're gonna get a localized response. It's a little piece of wood or metal.

    7. AM

      Yeah.

    8. AH

      And so you're gonna get the innate response, and you're gonna get some pus around it, and it'll kinda localize the wound. But when it comes to an invasive virus like the cold virus, uh, it overtakes us, right?

    9. AM

      Yeah.

    10. AH

      The production of mucus, we get the headache, like the... And I think it's the systemic effect that, um, that intrigues me so much. Like it, w- where is the signal to j- to, to launch a systemic versus a localized response in the immune system? How does it determine that?

    11. AM

      You know, I think some of it depends on, on what virus we're talking about, w- w- 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 sys- 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 w- are essentially chemical signals that something is wrong.

    12. AH

      Mm-hmm.

    13. AM

      Major ones are, they're called cytokines.

    14. AH

      Mm-hmm.

    15. AM

      And they can act locally, but they can also have more distributed effects. And some of the things that, that the cytokines can do can influence w- 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 of the b- 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 s- maybe the fever gives us some edge in fighting sort of some, some types of infection, but it also makes us feel lousy.

    16. AH

      Mm-hmm.

    17. AM

      And so the, you know, the, the, the immune system is, is always walking the... I think in sometimes the immune sys- immune system response to infections is too strong.

    18. AH

      Mm-hmm.

    19. AM

      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.

    20. AH

      Thank you. One of the reasons I ask that is, well, I hate being sick.

    21. AM

      [laughs]

    22. AH

      Uh, 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.

    23. AM

      Yeah.

    24. AH

      Antibiotics are amazing.

    25. AM

      Yeah.

    26. AH

      I've had a few things where I was like, "Oh, this thing's bothering me," and, uh, like I had this sinus infection a few years back, and I was like, "Oh, 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 over-prescribed-

    27. AM

      Yeah

    28. AH

      ... 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 of, or the intensity of some sort of infection? Because surely you're short-circuiting 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, uh, y- allowing your immune system to do the work and going through the misery of being really sick and infected?

    29. AM

      I don't think so.

    30. AH

      Great. Okay.

  9. 30:51 – 38:27

    Cancer; Mutations & Cell Regulation; Smoking, BRCA Mutations, Sunlight

    1. AH

      Um, I-I want to understand the relationship between the immune system and cancer.

    2. AM

      Yeah.

    3. AH

      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 not so distant 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?

    4. AM

      Yeah. Yeah. I mean, if anyone's really interested, I, I would highly recommend th-this book, uh, The Emperor of All Maladies-

    5. AH

      Mm-hmm

    6. AM

      ... which is a, uh, which is really a biography of cancer as a disease.

    7. AH

      Mm-hmm.

    8. AM

      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 sophisticat- 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 te- 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 sk- a skin cell. In cancer, all of a sudden some combination of mutations emerge in that cell that lose its normal regulation. It do- 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 i-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 d- 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 their normal pro-pro, uh, regulation and are dividing out of control in various tissues.

    9. AH

      I can see the picture in my mind where a otherwise healthy cell gets a mutation. We can talk about how mutations arise.

    10. AM

      Yeah.

    11. AH

      But, and then starts, uh, spitting off daughter cells-

    12. AM

      Yeah

    13. AH

      ... as it's referred to.

    14. AM

      Yep.

    15. AH

      Why would the daughter cells inherit the mutation necessarily to then create more cells? Because that's the proli-proliferation of the tumor.

    16. AM

      Yeah.

    17. AH

      Certainly, cells propagate their DNA into their daughter cells. But, um, it, 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?

    18. AM

      Yeah.

    19. AH

      And they don't create more cells.

    20. AM

      Yeah.

    21. AH

      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?

    22. AM

      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 gonna replicate, the DNA has to replicate itself. So you end up with two copies of DNA w- that should be the same-

    23. AH

      Mm-hmm

    24. AM

      ... 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 deleterious 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.

    25. AH

      Yeah, they can't take up glucose.

    26. AM

      Yeah.

    27. AH

      They can't re- they just can't do cell stuff.

    28. AM

      And there's a lot of control mechanisms in the cell that say something, if something's wrong, let's send a, a program cell death signal to that cell.

    29. AH

      Mm-hmm.

    30. AM

      And cells will kind of implode with, with various processes-

  10. 38:27 – 42:33

    BRAC Mutations, Mutagens, Pesticides

    1. AH

      yeah, the BRCA mutation, I, I have a personal relationship to this 'cause I lost both my graduate advisor and my postdoctoral advisor to BRCA mutation-related cancers ver- fifty and si- you know, just a little bit older than sixty in the other and, you know, brutal, um, especially when you're, you know, one of them I know their kids and, you know, it's, um, uh, just for young people getting cancer, and I know they're childhood cancers, but BRCA seems pretty common.

    2. AM

      I don't know the numbers-

    3. AH

      Mm

    4. AM

      ... off the top of my head. I mean, I-- they're not the major, like, numerical causes of, of-

    5. AH

      Mm

    6. AM

      ... of cancer. In the scheme of cancers that develop, it's, 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 BRCA 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. Um-

    7. AH

      And we can all get tested for it-

    8. AM

      Yeah

    9. AH

      ... now pretty cheaply, right?

    10. AM

      And, and, yes.

    11. AH

      Yeah.

    12. AM

      Yeah. That's certainly recommended if there's a family history of, of cancer for BRCA mutations and a co- a co- a couple of other ones, but you're right. It's the tests are available. And you asked about men v- and women.

    13. AH

      Mm-hmm.

    14. AM

      It actually was, was men were s- were some of the ways that those BRCA genes were identified.

    15. AH

      Mm.

    16. AM

      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.

    17. AH

      Interesting. Um, everyone, get tested for BRCA if y- y- you know, because there are lifestyle factors that can-

    18. AM

      Yeah

    19. AH

      ... reduce your cancer risk. I'd like to talk about mutagens.

    20. AM

      Yeah.

    21. AH

      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.

    22. AM

      [laughs]

    23. AH

      Uh, the battle to sort of protect vaping is, is, like, beyond me, but, um, okay. To each their own. Um, environmental, uh, sort of and workplace hazards, you know, like known mutagens. If you work in a laboratory-

    24. AM

      Yeah

    25. AH

      ... you're working with mutagens.

    26. AM

      Yeah. [laughs]

    27. AH

      Right?

    28. AM

      Yeah. Yeah.

    29. AH

      God, you're working with things that literally pull DNA apart.

    30. AM

      Yes. Yeah.

  11. 42:33 – 43:57

    Sponsor: AG1

    1. AM

      risks are.

    2. AH

      As many of you know, I've been taking AG1 for nearly fifteen years now. I discovered it way back in two thousand and twelve, 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 drinkag1.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 drinkag1, with the numeral one, .com/huberman to get six free travel packs and a bottle of vitamin D3 K2

  12. 43:57 – 49:34

    X-Rays & Airport Scanners, Carcinogen vs Mutagen, Charred Meat, Food Dye

    1. AH

      with your subscription. I get X-rays at the dentist now and again.

    2. AM

      Yeah.

    3. AH

      But I prefer not to get them.

    4. AM

      [laughs]

    5. AH

      X-rays cause mutations.

    6. AM

      Yeah. Again, uh, there's a trade-off and-

    7. AH

      Mm-hmm

    8. AM

      ... the dose and-

    9. AH

      Sure

    10. AM

      ... I, you know, when you need an X-ray, you need an X-ray.

    11. AH

      Mm-hmm.

    12. AM

      But I wouldn't do them for fun.

    13. AH

      Right. Um, I mean, I have colleagues who-

    14. AM

      Yeah

    15. AH

      ... prefer to do the slower, um, manual, uh, pat-down at the airport-

    16. AM

      Yeah [laughs]

    17. AH

      ... um, to going through the scanner. It's a low level of radiation-

    18. AM

      Yeah

    19. AH

      ... 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-

    20. AM

      Yeah

    21. AH

      ... 'cause they're, you know, uh-

    22. AM

      Mm

    23. AH

      ... 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 cancer. Okay, there's a bunch of things there. But, um, do you yourself avoid the scanner at the airport?

    24. AM

      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 can avoid it [laughs]

    25. AH

      Mm-hmm

    26. AM

      ... I, I try to minimize.

    27. AH

      Mm-hmm.

    28. AM

      But I... That's not based on some inside knowledge I have, but I have the same-

    29. AH

      Mm-hmm

    30. AM

      ... bias of-

  13. 49:34 – 59:04

    Immune-Based Cancer Treatment, Checkpoint Inhibitors, CAR T-Cell Therapy

    1. AM

      Now, what I, I think we can also talk about is, well, like, how, how do we handle, how do we treat cancer- Mm-hmm ... when it comes up? And this is where these two conversations that we've been having really come together- Mm-hmm ... 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- Mm-hmm ... the dogma was, "Don't waste time thinking about cancer immunology. G-cancer immunology is a field that's going nowhere." Hmm. And, I mean, I think, uh, I w- I w- I was in Boston, and 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. Mm-hmm. At that point, the, the way that 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 s- more toxic to the cancer cells than to the healthy cells and p- 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 wanna 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. Mm-hmm. 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 n- we've really measured th- 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, um- So these are cell cycle inhibitors S- uh, signaling- Mm-hmm ... the thing, various mutations affect th- these growth properties of, of cells, and there's targeted drugs that have been designed to go after some of those p- pathways that are making the cells divide out of control. Mm-hmm. Yeah. In... I think that benefit has come, but cancer has ways of mutating around that and can become, developing resistance, the same way we talked about resistance in bacteria to antibiotics if they're expo- you could ... Cancer cells are, can evolve quickly- Mm-hmm ... 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 talked, we j- 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 there. Can we unleash that immune system against cancer? And the hope would be that the cells of our immune system, we talked about how they're really exquisitely evolved- Mm-hmm ... 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. Mm-hmm. Now, that is not science fiction, and has c- is, is now approved and used to treat a number of different cancers. The first place where th- where this happened was in a class of medicines called checkpoint inhibitors- Mm-hmm ... um, or immunotherapy drugs. Uh, a lot of, a lot of r- people will have heard of these things. PD-1, CTLA-4 are some targets where there are drugs that get infused that hit these things that are on the surface o- of T cells, and, uh, they actually are natural breaks to the T cells. T 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 T cells, the T cells go stronger, and they can be unleashed against cancer just by taking the breaks off of them. What sorts of cancers has it- So the- ... been successful for? ... the poster child for this has been melanoma. Mm-hmm. One of the big success cases was, was Jimmy Carter, who had a melanoma, which is a skin cell, ag-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, uh- Amazing ... and so, you know, there was, you saw these tumors just shrink away. And, and, and not just him, but in a h- in a large fraction of, of melanoma patients now respond to these. Mm-hmm. And so that, that has changed how melanoma is treated. It's ... And other cancers, to varying degrees, s- some types of cancers can respond to this. That's taking the, a drug that unleashes the T cells that are already in our body. The focus of my research then is, well, I j- w-well, first thing I said was we're living in this amazing moment of biology where we can im- 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 T cells that are naturally in our body that already have this random distribution of sensors. We can actually genetically make a, a, a, one of these sensors for T cells and put it into T cells. We, we can put in a, put a gene that encodes something on the surface of T cellsThat will make them programmed to search and destroy for cancer cells. Now, this is, this is largely known as chimeric antigen receptor T cells. That's a, a long term. They're known for short as CAR T cells, chimeric antigen receptor. And what that means, chimeric, 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 T 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 T 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.

    2. AH

      Mm.

    3. AM

      The thing that woke up me and the world was in two thousand twelve, there was a young girl who was the first pediatric patient to be treated with a CAR T 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 res-- It, it just was, for some reason, whatever reason, it failed all the treatments, and th-it just nothing worked. She was gonna be sent home on hospice. She had, uh, exhausted all the possibilities at the age of eight. And she got enrolled in a, at that time, highly experimental treatment to get these CAR T cells. So her blood cells were taken out in a big blood donation. Her t-own T cells were genetically modified, and we can talk about how that was done. It was actually done with like a pretty crude technique that's been around, actually used viruses, lentiviruses, th-these are sort of modified HIV viruses, to deliver this extra piece of DNA that encoded the CAR. And this w-was done on her cells, and then after that extra gene was put into the T cells, the T 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, uh, 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.

    4. AH

      Amazing. And the lentivirus itself didn't, uh, didn't spark a, an immune reaction that was-

    5. AM

      No.

    6. AH

      That outweighed the benefits of the-

    7. AM

      No

    8. AH

      ... of the cargo.

    9. AM

      No. It, ama-amazingly, it, it really hasn't. I mean, th-there, there's been some discussion about the risks of using these lentiviruses.

    10. AH

      Mm-hmm.

    11. AM

      And we, we'll talk in a second about how we can do better now.

    12. AH

      Mm-hmm.

    13. AM

      But-

    14. AH

      Yeah, people are gonna 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-

    15. AM

      Yeah

    16. AH

      ... so they're not delivering HIV. Uh, these viruses are incredible because they can create long-lasting expression of genes that you deliberately put into them. They're, they're a shuttle.

    17. AM

      It's an amazing application of biological understanding-

    18. AH

      Mm-hmm

    19. AM

      ... right? That all of a sudden we've been studying viruses because of the risk that they have. We-- But we've learned that they can deliver-- that, that viruses have evolved to be very good shuttles-

    20. AH

      Mm-hmm

    21. AM

      ... and to deliver their genetic material into cells.

    22. AH

      Mm-hmm. The way I think of it, uh, the, is the viruses have evolved to take advantage of our biology and our genes.

    23. AM

      Yeah.

    24. AH

      And so we did it the ultimate touche in these instances. Like, you're so good at, at hijacking our cells' DNA and proliferating, all right, we'll leverage you-

    25. AM

      Exactly

    26. AH

      ... to help us as opposed to hurt us, right?

    27. AM

      That's exactly right.

    28. AH

      Mm-hmm.

  14. 59:04 – 1:02:52

    CRISPR, Immunotherapies

    1. AM

      And so that was done in two thousand twelve. Emily Whitehead was eight. It was d-done as an experimental treatment at the University of Pennsylvania. And the story now is that now, all these years later, Emily Whitehead is not only cured of her leukemia, she's pre-med at the University of Pennsylvania. [chuckles]

    2. AH

      So, so awesome. So awesome.

    3. AM

      And so, like, no one could ignore this.

    4. AH

      Mm-hmm. Mm-hmm.

    5. AM

      You know, this was, this wasn't, this was just all of a sudden, uh, this dogma that I had just been taught a couple of years earlier in medical school that we should ignore th-the cancer immunotherapy. It was just, we were just wrong.

    6. AH

      Mm-hmm.

    7. AM

      And all of a sudden, the field woke up and said, "Okay, the immune system is not just limited to treating vi-viruses and bact-- or protecting us from vi-vari- 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 two thousand twelve. Two thousand twelve also was the year that a paper got published in Science by Emmanuelle Charpentier and Jennifer Doudna that introduced this new technology called CRISPR. And we can t-- we, we, we'll talk about this, but CRISPR fundamentally is a tool to rewrite DNA sequences. That came out in two thousand twelve. And, uh, on a personal level, two thousand twelve was also the year that I moved to San Francisco to start a lab studying T cells and how genetics influences T 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 T 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 T cells and use CRISPR 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 CRISPR technology, get it to work in T cells, to learn the rules about what are the genetic changes that will be most effective at making T cells intointo immunotherapies that cure patients for di- with different diseases.

    8. AH

      It's amazing.

    9. AM

      And then to go all the way and then actually use CRISPR to make T cells that can be in-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 CRISPR engineered CAR T cells, and we're not just going after leukemias, where these CAR T cells have historically worked, but, uh, 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 T cells to find the right targets in tumors and then work inside of tumor environments, which are inherently immunosuppressive, requires figuring out additional gene edits that are now possible with CRISPR 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 CRISPR, we can think about getting one step ahead and making T cells that are able to be-- resist all the tricks that cancers throw at it to be more... And the t-- I think we're on the brink of having precise CRISPR engineered cells that will, I, I hope, start to melt away cancers without the side effects of chemotherapy.

    10. AH

      Amazing. Uh, just amazing. And the story of this young woman is spectacular. Um, I have two questions before we talk about CRISPR technology.

    11. AM

      Yeah.

    12. AH

      The

  15. 1:02:52 – 1:08:27

    Age & Cancer Risk; CAR T-Cells, Targets & Side Effects; Ketogenic Diet

    1. AH

      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, y- so that's the first question. And then, uh, the other question has to do with how, uh, the, the immunotherapy that you described, um, was able to target the cancer and, and not cause problems elsewhere-

    2. AM

      Yeah

    3. AH

      ... which is kind of the major issue of chemo and, and radiation therapy. But the first question, um, again, was, you know, why more, um, mutations as we get older?

    4. AM

      So I think there's, there's a few cancers that, that peak in childhood, and there's t- risk as, as the body's developing of certain cancer, childhood cancers, and there's childhood leukemias, for example, then that, like when we talk about Emily Whitehead. But most cancers, as you said, exactly as you said, the- 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- cert cells start to accumulate mutations. Numerically, a lot of those cells that have the mutations will die off, and it's just a, 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-

    5. AH

      Mm-hmm

    6. AM

      ... is, is, is, is a big factor here. Time and just accumulated damage.

    7. AH

      And the other question was, you know, how is it that the lentivirus knows to, um, [lips smack] the lentiviral, uh, cargo carrying T cells, uh, know to attack the cancer and not something else?

    8. AM

      So this is a key question for the field, right? Is-- And I think one of the things that worked incredibly well was a brilliant choice by a group of scientists in differ- a few different places that converged on the target that was used in the first CAR T cell. And what the target is known as i- is, is a protein called CD19.

    9. AH

      Mm-hmm.

    10. AM

      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 leukemias themselves are a dise-- a, a cancer of the immune cells, so they're a cancer of B cells, and CD19 is, is found on the c-- on the surface of many, a, a, a, a large number of different types of B cell leukemias and lymphomas.

    11. AH

      I see.

    12. AM

      I think one of the things that turns out to be serendipitous here is that B, B cells themselves, natural, healthy B cells actually also h-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 s-safe and relatively well-tolerated treatment for cancer is that the collateral damage is actually not that damaging. The T 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 l- 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 th-think about pancreatic cancer or brain cancer, finding targets that if you hit the hank-- 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 h-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.

    13. AH

      Mm-hmm.

    14. AM

      Like c-- the T cell will only kill cancer if it finds this and this-

    15. AH

      Mm-hmm. Mm-hmm

    16. AM

      ... and th-that combination of things are not found on, on healthy cells, even if one or, or the other might be. So people are thinking about-

    17. AH

      Mm-hmm

    18. AM

      ... how do we get more sophisticated about building these discrimination systems i-into T 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.

    19. AH

      Awesome. Before we talk about CRISPR, there was one other question that I know many people will be thinking about. Uh, a few years back, maybe five, 10 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 wanna bold, uh, underline and, and capitalize perhaps, ummight help, but for other cancers, it could make things worse. And then, uh, I also more recently started hearing about, uh, low-glutamine diets.

    20. AM

      Mm.

    21. AH

      Um, so, and of course, this is the way the internet works.

    22. AM

      Yeah, yeah.

    23. AH

      But, um, but I did see some papers in some decent journals, you know, uh, that at least were exploring this. So are, um, low... They're just low car- let's call it what they are, ketogenic diets, um, have they been shown to be useful for treatment or avoidance of cancer?

    24. AM

      I have to defer to you. I actually, I don't, I don't know the answer to that, yeah.

    25. AH

      Okay. My, my guess is that, um, people are still looking at this.

    26. AM

      Yeah.

    27. AH

      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 III diabetes.

    28. AM

      Mm.

    29. AH

      But my understanding from talking to the experts in this is that, um, it might help through indirect mechanisms, but that it's not gonna solve the problem. Um, okay. Well, th-thanks for entertaining that little, uh-

    30. AM

      [laughs]

  16. 1:08:27 – 1:17:06

    CRISPR Discovery & Mechanism

    1. AH

      CRISPR. Tell us the story of CRISPR. Uh, because I think CRISPR 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.

    2. AM

      Yeah.

    3. AH

      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 CRISPR is actually also a story about, uh, how science works.

    4. AM

      Yeah.

    5. AH

      And that's important, too.

    6. AM

      I think it's e-exactly true. I think it is a perfect illustration of something where a discovery happened without-- no one was planning-

    7. AH

      Mm-hmm

    8. AM

      ... but changed biology. Um, uh, let me tell this story in two separate arcs. One arc is the arc of understanding DNA. You know, if, if you go back to Watson and Crick, it's understanding the double helix-

    9. AH

      Mm-hmm

    10. AM

      ... to understand the structure of w-the DN- what a DNA sequence is. That matures. We've learned how to sequence to understand the r- to be able to measure a row of A, Ts, and Cs, and Gs 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 two thousand, 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, a milestone for, for biology and medicine. And then se- DNA sequencing technologies continue to improve and cost comes down, and 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, uh, between people with DNA at the level of at least statistics. Okay, people with this disease are m-more likely to have this, this gene than that, but we're getting to some limit of what we can do just by m- sequencing DNA. All of a sudden, you're, 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, w-we're desperately looking for a tool to say, "Well, now we wanna-- as we have all the sequences, we wanna be able to see what happens if you change a sequence." And people were stumbling around looking for w- different tools. There were, there was, there was a, a range of these things. There were zinc fingers. There... 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 in cells, and it had been a long-standing effort. Out of nowhere emerges CRISPR as the answer to this problem. CRISPR was being studied as an, 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 repea-repeat sequences actually ba-- formed the basis of a kind of immune system for bacteria.

    11. AH

      Mm.

    12. AM

      Now, we talked about the human immune system.

    13. AH

      Mm-hmm.

    14. AM

      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, right?

    15. AH

      Everyone's trying to kill everyone else. [laughs]

    16. AM

      And so bacteria are constantly being bombarded by certain types of viruses. They're called bacteriophage viruses, and they've evolved a, a series of... Bacteria have d- evolved a series of defense mechanisms to protect themselves from, from these viruses. CRISPR turns out to be a bacterial defense mechanism against viruses, which is kind of amazing that this-

    17. AH

      Mm-hmm

    18. AM

      ... that this thing that has entered into popular culture is-

    19. AH

      Mm-hmm

    20. AM

      ... a bacteria protection against bacteriophage. Now, why has this caught the world of biology by storm? Well, what was realized was that the way that, that CRISPR works to protect against itself, uh, to, um, protect bacteria from viruses is that it can recognize particular sequences of DNA, which are virus sequences, and dis-discern, discriminate whether it's a virus sequence or its own bacteria sequence.

    21. AH

      Mm-hmm.

    22. AM

      And it actually does that by scanning across the DNA and finding something that's recognized as a virus target, uh, 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 Jen-Jennifer Doudna and Emmanuelle Charpent-Charpentier, many people around the world have contributed to this field, um, what was realized was that this could be repurposedAs a tool, if we take it out of bacteria, we could actually exploit this CRISPR system that had evolved to protect bacteria. And the same rules that allowed bacteria 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 CRISPR. 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, that you don't want to be in a cell. You can start pasting in sequences to replace mutations that cause disease. You can start pasting in big sequences like the sequence for CARs or other types of things that will make T cells more powerful. So, and this is, I'm focused on T cells, but this is 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 every organ system to understand every type of disease and to build new types of molecular medicines. There's one other feature of CRISPR that's really important in this story. It's not just that this CRISPR can cut at a specific sequence, that it's evolved to cut at virus sequences. 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 CRISPR, if you think of it as an enzyme that can cut DNA, and 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 CRISPR, sometimes called Cas9, which is a particular type of CRISPR system, um, 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 what's so special about that is that we actually know with perfect, near perfect precision the rules of how an RNA will recognize any DNA sequence. There's a complementarity where 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 the lab in a matter of days. We mix it with Cas9 protein, and then that's going in T 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 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 targeted CRISPR 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 happens to the cell? 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 CRISPR modified cells all the way and infuse them into patients.

  17. 1:17:06 – 1:20:57

    CRISPR Precision, Risk & Benefit; CRISPR Technology Evolution

    1. AH

      Incredible. And thank you for that incredibly clear and detailed explanation of the CRISPR-Cas9 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 a related question is if you're going to introduce a gene sequence there, how do you ensure that there aren't downstream effects?

    2. AM

      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 CRISPR of 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 off targets, right? If you're programming to cut on one place on chromosome six, 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 at one place." There are still the second risks of bystander effects. Okay, you make a cut, what, does the DNA get chewed back at the neighboring part? There's been, in some extreme places, pieces of chromosomes actually falling off. 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 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 CRISPR world is not static.

    3. AH

      Mm-hmm.

    4. AM

      And what I, the story I told you was like the building block of CRISPR. 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."

    5. AH

      Mm-hmm.

    6. AM

      Maybe that CRISPR 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 Liu at Harvard has created these things called CRISPR base editors that doesn't introduce a double-stranded break, but actually changes nucleotides in a more predictable way at that site by recruiting adeaminase domain, something that will change DNA nucleotides when it's recruited to a particular place, and you use CRISPR just to recruit that enzyme that makes that mutation at a targeted place. Other people have actually started using epigenetic enzymes. The 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 As and Ts and Cs and Gs. And now we and other u- others are using CRISPR-based epigenetic editing.

    7. AH

      Mm-hmm.

    8. AM

      It's called epi-editing, 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 h- mitigating some of these 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

  18. 1:20:57 – 1:22:17

    Sponsor: LMNT

    1. AM

      way.

    2. AH

      I'd like to take a quick break and acknowledge one of our sponsors, LMNT. LMNT 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 LMNT 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 sixteen to thirty-two ounces of water with an LMNT packet dissolved in it. I also drink LMNT 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. LMNT 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 LMNT, you can go to drinklmnt.com/huberman to claim a free LMNT sample pack with any purchase. Again, that's drinklmnt.com/huberman to claim a

  19. 1:22:17 – 1:33:47

    CRISPR Cell Delivery, Clinical Trials; Treating Early Cancers & Prevention

    1. AH

      free sample pack. I'm curious about getting CRISPR into the cells of interest.

    2. AM

      Yeah.

    3. AH

      You know, the lentivirus example that you gave before, um, my understanding is it involved harvesting some T cells, um, introducing the lentivirus with the, with the cargo that you want, putting that back into circulation, and the T cells know where to go and know what to do. Uh, for a lot of cell types like neurons in the brain-

    4. AM

      Yeah

    5. AH

      ... 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 fro- you know, without having to be so invasive. Um, so wh- what's being done there in terms of trafficking, um, CRISPR to appropriate cell types or, and/or organs, and then that, uh, sort of seeds another question that I'll, I'll hold off on about whether sh- we should be banking, uh, cells or, or, um, for what's coming.

    6. AM

      First of all, I just want to pause for... This, this is, this is great. I love this conversation. [laughs]

    7. AH

      No, I do too. I mean, you're taking us to the, the, I don't like the phrase bleeding edge. It sounds violent, but you're taking us to the cutting edge of molecular biology and medicine, and w- we are peering over into what's next, like what your children and my children and, uh, probably our parents also will, uh, be able to benefit from in the next ten years, maybe sooner.

    8. AM

      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 is I think you asked one of the key questions for this field of how is this being delivered into cells.

    9. AH

      Mm-hmm.

    10. AM

      So I, I told you, let me go backwards and then I'll go forward. I told you that in two thousand twelve, I sort of was sitting there thinking about I wanted to study T cells, the genetic control of T cells. I saw the power of CAR T cells. I saw the power of CRISPR, which at that time was being only used in highly artificial immortalized cell lines that grow easily in the, in the lab. And it just wasn't clear that there would be a way to get CRISPR to work in real T cells that you would take out of a human blood sample that are not immortalized, that can only stay in a dish for a short amount of time and still retain their function. And I put a, I, I sort of tripled down on this was what my lab was gonna do, that we were gonna figure out a way. And we went through a long list of different ways that we might deliver, and it wasn't obvious. Actually, a key collaboration early in my career was t- another serendipitous run-in with... I met Jennifer Doudna through some persistence of my own, and Jennifer Doudna and I sat down and started thinking about how could we team up to take her expertise in CRISPR biochemistry and get it to work in T cells. And we settled on this, this thing that was not at the top of my list of things that would work, but ended up opening up the field. We actually purified the, the CRISPR protein. So we had protein and RNA that would, we, we could make in a test tube. Now, now we order it off the internet. We can mix them together, and we could make these protein RNA complexes, and we could suspend that in liquid. And then what we did is we actually incubated T cells from a blood sample in that liquid. And then the question was, how do you get these protein RNA complexes into the cells? And we used this trick that's been around for a long time. No one ev- as, as long as it's been around, sounds magical, and no one quite understands how it works. We put the cells into a device that gives a small electrical current to the T cells.

    11. AH

      Electroporation.

    12. AM

      Electroporation. [laughs]

    13. AH

      Oh man, I, I-Like during my graduate career, I electroporated a lot of, well, I can just say it now because I don't do it anymore, um, electroporated a lot of brains of, uh, of i-intact animals.

    14. AM

      Yeah. Yeah.

    15. AH

      You inject DNA, it's floating around in the, in the local tissue. You pass some square wave current.

    16. AM

      Yep.

    17. AH

      And the assumption is that it creates little transient pores in the cell membrane, and so it gets in, and sometimes you end up with four cells, uh, transfected, and sometimes you end up with forty thousand cells transfected. It's a wildly useful technique, but it's a little bit hit or miss.

    18. AM

      That's perfect description. And so we, we s- my first postdoc in my lab, Katherine Schumann, sat there and tested different electroporation conditions, altering these little pulse codes that-

    19. AH

      One pulse, twelve pulses, long pulse. You're taking me back to my graduate and, and to some extent my postdoctoral years. It's unclear for given tissues, for given, uh, sequences, what's gonna go into cells, what's gonna not kill the cells.

    20. AM

      We were walking this tightrope of how do you make this pore is big enough that CRISPR will get in, but that the cells don't die. And we did it, you know. And we did it, and we've wor- we've optimized this. And it was one of those things you, when it happens, you, you see it and you just realize it's, it's binary. Like all of a sudden, you're, you're editing DNA inside of, of T cells. And, you know, we got our foot in the door with some level of efficiency. We've gone through the roof. This is now used by labs widely, and it's incredibly efficient. And some cells die, but overwhelmingly, you end up with cells that, that are gene edited.

    21. AH

      She figured out the protocol.

    22. AM

      Yeah. She really did. And it's been optimized. And then another grad student in my lab came in, this guy, amazing grad student, Theo Roth, and realized that he didn't have to stop there, that we thought we were limited to just putting CRISPR in and these very small pieces of DNA called oligonucleotides that would just change a couple of nucleotides at a time. Our mindset was like, maybe we can fix a mutation, an individual mutation. Theo said, "Let's not stop there. Let's put big pieces of DNA in." And we've pushed this boundary of being able to say, "Let's pick a site, make a cut, and introduce hundreds or up to thousands of different nucleotides to be able to really write a piece of DNA code that doesn't even have to exist in nature, but then we have the precision using CRISPR to put it into a particular place in the DNA." We started a company when that, when that technology worked, a company called Arsenal Biosciences that's now in clinical trials. It's actually in, it's in its clinic- third clinical trial right now for solid tumors. It's in a clinical trial for prostate cancer that's about to start enrolling patients. And that company can now do this at industrial scale. It takes patient cells, electroporates them, and has now written a long piece of like ten, ten thousand nucleotides of DNA code that put in a sequence of a combination of different receptors-

    23. AH

      Mm-hmm

    24. AM

      ... including a CAR, and additional gene enhancements that will make these T cells more powerful in, in, in a tumor microenvironment.

    25. AH

      And then they go into the bloodstream, they navigate to the prostate-

    26. AM

      Yeah. Sure

    27. AH

      ... and they start fighting the cancer cells. And I imagine you can also put... It sounds like you're putting some, um, kind of resilience genes in there as well-

    28. AM

      Yeah. Exactly. That's exactly right

    29. AH

      ... to bolster the healthy cells.

    30. AM

      To bolster the, the t- the T cells that carry these receptors-

  20. 1:33:47 – 1:39:57

    Liposomes, Engineered Viruses, Lipid Nanoparticles (LNPs), Vaccines

    1. AM

      fast.

    2. AH

      You know, when I was a postdoc, there was a, it was all about, it seemed [chuckles] for a few years, like, different ways to get genes into cells.

    3. AM

      Yeah, yeah.

    4. AH

      Um, so there's electroporation.

    5. AM

      Yeah.

    6. AH

      There are lentiviruses.

    7. AM

      Yeah.

    8. AH

      There are adenoviruses.

    9. AM

      Yeah.

    10. AH

      There are, um, calcium phosphate transfection. There was, and on and on. One of the things that was kind of interesting, but at the time didn't really go anywhere, was, um, customized little, uh, liposomes.

    11. AM

      Yeah.

    12. AH

      Like little fatty bubbles-

    13. AM

      Yeah

    14. AH

      ... 'cause fatty stuff can get onto-

    15. AM

      Yeah

    16. AH

      ... and through cell membranes, so it makes good sense. But, but with some sort of zip coding so that you could inject these fatty bubbles, um, or swallow them even, get them into the bloodstream, and then those fatty bubbles would go to the very specific type of liver cell or brain cell that you wanted. Has that technology moved forward at all, the liposome technology?

    17. AM

      Dramatically.

    18. AH

      Oh, great. [laughs]

    19. AM

      Dramatically. [laughs]

    20. AH

      Relieved, relieved to hear and relieved to hear I wasn't the one that had to do the work. 'Cause I knew a lot of very frustrated people working on liposomes. Fortunately for me, electroporation adenoviruses worked spectacularly well for my experiments, but a lot of people needed cell type specific in, um, transfection-

    21. AM

      Yeah

    22. AH

      ... through a, a vein injection.

    23. AM

      So all of these things have gone under rapid progress. The vi- let's talk about the viruses.

    24. AH

      Mm-hmm.

    25. AM

      We talked about viruses as a tool to delive-- as a shuttle of DNA. They naturally, each one will have some range of what cells it would infect. This is, for a virus, this, this is called tropism. What is, what cells are susceptible to infection with any virus, those would be the cells that you would be able to deliver g- genetic material to with an engineered virus. People have really advanced engineered tropism, engineering what cells a virus will deliver material to.

    26. AH

      Mm-hmm.

    27. AM

      And that can be dialed in quite precisely now in a number of different ways. So people are working on-

    28. AH

      Right

    29. AM

      ... engineered viruses that try-- There's still problems. They're trying to make sure that they don't trigger immune responses, but they're getting more and more precise, both viruses and things that have virus-like properties that are sometimes called virus-like particles-

    30. AH

      Mm-hmm

  21. 1:39:57 – 1:47:51

    COVID Pandemic & Trust in Science, mRNA Vaccine

    1. AM

      of disease.

    2. AH

      I wanna just talk about the COVID vaccine briefly.

    3. AM

      Yeah.

    4. AH

      Um, because in my role as a public health educator, um, I was exposed to a lot of voices.

    5. AM

      Yeah.

    6. AH

      Um, and I can't speak for everybody-

    7. AM

      Yeah

    8. AH

      ... um, certainly, but I think that at least three of the things that caused a lot of divide around, um, the, the mRNA vaccines were, first of all, um, the difference between mandates versus optionality. We don't have to go there, but I think that-

    9. AM

      Yeah

    10. AH

      ... that was a, that was a major player, right? People, especially Americans, don't like to be told what to do. [laughs] That's just a-

    11. AM

      I've noticed that. [laughs]

    12. AH

      Okay. Second of all, um, it was closely related to, um, notions of the shutdown, which differentially impacted people, um, a-and that's an understatement, right? Pe- some people maintained paychecks, some people didn't. Some people could work, some people couldn't. So there was that. I just am, I, I'm not trying to, uh, you know, soften anything here, but I think that, that the vaccines were, were nested in a bunch of other issues, um, again, at least three. This is not exhaustive. And then the other one, and I actually had this concern myself, which was how is it that it gets turned off, right? Like I, I can imagine a situation where I would want to put, uh, an mRNA into me, um, to do something biologically, but then I don't want it to continue to do that after a period of time. So what in the design of that vaccine allowed it to be targeted to the cells of interest and then not continue to express in all other cells in perpetuity?

    13. AM

      I'll answer the specific question, but I think the context that you give is also a really important part of this, and I wa- I would take one second to talk about this. I think to, to, to answer your first question, we talked about DNA as the, the sort of source code. We talked about proteins as what the DNA is ultimately encoding. Let's just talk for a second about what mRNA is. mRNA is the sort of temporary intermediate between those things. DNA will get what's called transcribed into mRNA, which is another nucleic acid, but doesn't stick around permanently. It is the temporary instruction, which will then go to the ribosome and become the template, the, the template for a particular protein. The idea of an mRNA vaccine is that you're using this temporary template so that the cells that will take this up will make proteins from this temporary template for some period of time. Now, there could be some, I, you could always imagine the extreme outliers of ways that this could last longer or not, but fundamentally, this is, you're, you're putting in an mRNA that gives a temporary instruction to the cell to make a small part of the COVID vaccine. Now, of, of the COVID virus, very small part, right? Now, just by comparison, if you get infected with COVID, you're also gonna get COVID mRNA is transcribed in your cells. And, you know, the, that, that, that, so there's, we're talking about genetic material making mRNA either way, whether it's the mRNA from the COVID or a designed small part of that COVID vaccine, that if, of that COVID genome that we're using as a vaccine.

    14. AH

      Mm-hmm.

    15. AM

      So I think it's important to think about the risks in the context of the virus versus what we're doing with a, with a vaccine. So I got the COVID vaccine enthusiastically, and I, and I actually, I think overwhelmingly my immuno- I mean, I know overwhelmingly my immunology colleagues did the same. In people who live in this world of immunology, a, a great enthusiasm that this could be done and built. NowWell, that doesn't answer what you said about the cultural phenomenon. I'm talking just as a person-

    16. AH

      Sure, yeah

    17. AM

      ... not as an immunologist.

    18. AH

      Please, please.

    19. AM

      But I think we probably haven't done enough to talk about the trauma that we went through as a nation during COVID, o-of being fractured by people dying on one hand, and all the negative consequences, as, as you said, of, of shutdown. Shutdown of economic life, shutdown of social life. I, I, I think it was a period of major dislocation, and we're still feeling the trauma. And the people's different relationships with things like vaccine, but of science even more generally, were dislodged or accentuated by this trauma that I think we all collectively went through and we don't talk enough about.

    20. AH

      Mm-hmm.

    21. AM

      Um, I'll just, I'll just give one anecdote. Well, I, I spent a lot of time isolated during COVID and was disheartened by the fact that on one hand I was watching the sort of scientific, like, speed race that was, you know, actually I think one of the, one of the, the highlights of, of the first Trump administration, Operation Warp Speed, to, to streamline and get coordination both on the science and the, the regulatory side to get vaccines approved in an extraordinary timeline, taking advantage of a number of technologies and, and making them all. So I was watching this, this science unfold with some, some optimism, but also watching the trust in science being eroded. I developed a, a side hobby, um, which is I've been-- I've gone back. I've been reading, I've been reading presidential biographies sequentially. Uh, this is, this is, it's just a side hobby. Now, in this, in reading and thinking about this sort of frustration with, with how science was sort of tearing things apart, I found this sort of strange relief in reading about early American history. In 1793, there was a yellow fever epidemic in, in, in, um, in Philadelphia. And actually, the early parties that were forming, the, the Federalists and the Democrats, actually took, like, wildly dissenting views of how to deal with an epidemic. They, they had different views of what caused it, whe-whether it was outside contagion or those, or sanitation. And the, the Democrats of that, at that time, the Jeffersonian Democrats, were in favor of, like, really extreme, uh, bloodletting techniques, and the, and the Hamiltonians or the, or the Federalists had a, had a, a totally different set of techniques of baths and, and more gentle treatments, and they just couldn't see eye to eye. Why am I saying all this? I think it's not new territory, that in, in, that, that these discussions of how we deal with infections which are inherently societal diseases unearth the societal tensions, and we deal with them in different ways, and we come at to them from different perspectives. And there, there's a lot of things that are simultaneously being balanced in any decision of how we deal with thinking about the trade-offs that we're willing to make in the face of, of an, of a pandemic or an epidemic.

    22. AH

      I really appreciate that, and I'm also impressed that you're reading these biographies. How do you know which biography to select? Because there are many of them.

    23. AM

      [laughs]

    24. AH

      And unfortunately, Walter Isaacson hasn't written them all.

    25. AM

      Yeah.

    26. AH

      I love his books. So how do you select, uh, the author of each biography?

    27. AM

      This is, this is an odd... [laughs] This is a, a project that I spend a lot of time. Each one I, I go through a period of indecision about which one I-

    28. AH

      Okay

    29. AM

      ... I, I should read.

    30. AH

      Uh-huh.

  22. 1:47:51 – 1:49:39

    Sponsor: Function

    1. AH

      I'd like to take a quick break and acknowledge one of our sponsors, Function. Last year, I became a Function member after searching for the most comprehensive approach to lab testing. Function provides over one hundred advanced lab tests that give you a key snapshot of your entire bodily health. This snapshot offers you with insights on your heart health, hormone health, immune functioning, nutrient levels, and much more. They've also recently added tests for toxins such as BPA exposure from harmful plastics and tests for PFAS or forever chemicals. Function not only provides testing of over a hundred biomarkers key to your physical and mental health, but it also analyzes these results and provides insights from top doctors who are expert in the relevant areas. For example, in one of my first tests with Function, I learned that I had elevated levels of mercury in my blood. Function not only helped me detect that, but offered insights into how best to reduce my mercury levels, which included limiting my tuna consumption, I'd been eating a lot of tuna, while also making an effort to eat more leafy greens and supplementing with NAC and acetylcysteine, both of which can support glutathione production and detoxification. And I should say, by taking a second Function test, that approach worked. Comprehensive blood testing is vitally important. There's so many things related to your mental and physical health that can only be detected in a blood test. The problem is blood testing has always been very expensive and complicated. In contrast, I've been super impressed by Function's simplicity and at the level of cost. It is very affordable. As a consequence, I decided to join their scientific advisory board, and I'm thrilled that they're sponsoring the podcast. If you'd like to try Function, you can go to functionhealth.com/huberman. Function currently has a wait list of over two hundred and fifty thousand people, but they're offering early access to Huberman Podcast listeners. Again, that's functionhealth.com/huberman to get early access to Function.

  23. 1:49:39 – 1:55:45

    Drug Delivery to Cancer, Immunotoxins, T-Cell Engagers; AI Protein Targets

    1. AH

      I have a question related to technologies to killing or altering cells that we didn't cover, but since w- uh, we've touched on a number of them, the, uh, lip- lipid nanoparticles, um, lentiviruses, since we're, um...In a previous lifetime, I used, uh, in my experiments and I was excited by immunotoxins. So an antibody against you generally need a cell surface protein, and then you attach to it. In our, our case, we use saporin toxin, which, uh, I think is most infamous, uh, because it was put on the tip of an umbrella and used to assassinate somebody on a bridge someplace in some sort of, uh, international spy warfare in the last twenty years or so. Saporin will kill you if it goes systemic, but the idea there is that you take the saporin toxin and you tether it to an antibody that then finds a cell surface protein and then kills that cell and only cell. And it works remarkably well in experimental conditions if certain things are right. It doesn't always have the specificity you would like or the thoroughness. Um, has that been tried in cancer, um, directing toxins towards, uh, cancer cells?

    2. AM

      The short answer is yes. It's a, it's a really interesting area and, and it, and what that toxin is can almost be thought of as like modular, that you can put, uh, put a different-- That you can think of it as two components, right? You have a targeting component. You have in the, an antibody is a natural one where the antibody is evolved to recognize one particular type of protein. That can be the thing that targets something on the surface of cancer cells. Um, people have then developed what's called antibody drug conjugates, where basically a drug or a tox-- something that's gonna kill the cell gets appended to that antibody, and so s- it's selectively delivered. You don't have to deliver the drug at systemic doses, but you can actually increase the local concentration by delivering it preferentially to the cancer cells-

    3. AH

      Mm-hmm

    4. AM

      ... that will be recognized by that antibody. Doesn't have to be drugs. People are thinking about other things. We were, uh, when people are now trying to attach r- uh, radioactive isotopes, there's radioligand therapies that can be, that can be attached to these things. Um, and I think in an extreme, that's essentially what we're doing with these T cell therapies too.

    5. AH

      Mm-hmm.

    6. AM

      We're also using the, the-- When I- I've talked about this CAR, the chimeric antigen receptor, the outside of it that is the sensor that's being used is also an, a part of an antibody. And so essentially what we're doing is now using the antibody to target, but instead of dra- dragging along a drug, it's dragging along a cell.

    7. AH

      Mm-hmm.

    8. AM

      And so when that's engaged, the T cell is there, and the T cell becomes the killing module. But the ki- the cell not onl- the T cell not only kills the cancer cell, but could potentially be used to amplify that response, could recruit, re-release things and recruit other things. So I think this general way of thinking about designing things, um, to drag something to a cancer site is something that people are thinking a lot about. There's even another flavor of this that are called T cell engagers. So I talked about, okay, we can genetically put an antibody fragment on a T cell and use that to direct a T cell to a cancer. People are also making antibodies that are antibodies on both ends. Okay, so this is sometimes g- uh, I think this is a proprietary term, but it can be called a bispecific or a BiTE. Uh, the BiTE is a proprietary term. Um, but basically these are two-headed antibodies.

    9. AH

      Mm-hmm.

    10. AM

      One side will recognize a cancer cell, and the other side will recognize a T cell and essentially bring these things together-

    11. AH

      Mm-hmm

    12. AM

      ... so that you get the T cell action locally to the cancer cell without having to do any genetic mod- modification to the T cell. You actually just take advantage of T cells that are-

    13. AH

      Mm-hmm

    14. AM

      ... already in the body. So all of these things are now under very active development and, and some of them are approved, others are still in development.

    15. AH

      Very cool. I'm sure people are catching on to this, but basically if you can understand the structure of things, including very, very small things, you can Lego them-

    16. AM

      Yeah

    17. AH

      ... and you can, um, put all sorts of interesting cargos and play matchmaker between cells and, um, uh, it's kind of infinite what, what you can do, um, once you start to understand things at that scale. That's really what it's about.

    18. AM

      I'll push it one step further. I'm, I'm actually, uh, helping to organize a cancer immunotherapy conference here in, in LA. I'm, I'm simultaneously here for-

    19. AH

      Mm-hmm

    20. AM

      ... for this and for that. I was at the conference yesterday, and there was a talk by Amgen, big pharma company. I should disclose, I'm, I'm an advisor to Amgen, but this, this talk was-- And Amgen's been one of the leaders in these BiTEs. I, I think they actually trademarked this idea of bispecific T-cell engager. Um, these are antibody fragments, but, uh, one of the leaders at Amgen talked yesterday about how looking forward, these aren't being used as just traditional antibodies that come out of, of animals, but they're actually being used as AI-designed protein engagers of any target you want. So essentially now it's getting to the point where if you know that something's on the surface of a cancer cell, people are increasingly using AI models to design a synthetic protein that doesn't even exist in nature, that is designed to recognize and stick to something on the surface of cancer cell, and that could be one of these Lego blocks-

    21. AH

      Mm-hmm

    22. AM

      ... for these modular multi- multifaceted in T, uh, cell engagers or drug engagers or any of these other things. So this is another area where the, the crosstalk between experimental capabilities and computational expe- expe- uh, capabilities is further ac- accelerating what's possible.

  24. 1:55:45 – 2:05:42

    CRISPR Embryo Modification, Ethics; Heritable Gene Editing, Diversity

    1. AH

      Incredible. Um, would you mind if I asked a couple of questions about the kind of science, sociology, and, uh, ethics around CRISPR?

    2. AM

      No, I'd, I would love it.

    3. AH

      I'll keep this brief.Um, a few years back, uh, we all learned, meaning the entire world learned, that, uh, a scientist in China had done a CRISPR-Cas experiment on babies.

    4. AM

      Yeah.

    5. AH

      I don't know when he did the modification. My guess is it was in utero, but you'll tell us what exactly he did. This hit close to home for me because he and I were postdocs at the same time at Stanford, different labs, and the way it, the news hit the world was very interesting. One of the things I benefit from now as a podcaster and not just a professor is that I can talk about the stuff that perhaps pure professors wouldn't be willing to, um, so I'll say it. It was very interesting because the world kind of braced but didn't make a decision as to whether or not they were upset that he had done this, like put him in front of an ethics board, maybe even throw him in a cell, or give him a Nobel Prize.

    6. AM

      Yeah.

    7. AH

      It was like there was this kind of moment where no one really knew what to do.

    8. AM

      Yeah.

    9. AH

      Like, do you reward him? Do you punish him? Do you do nothing? And it circulated back to Stanford because there was a question of, you know, what he had learned at Stanford, what was done at Stanford, and, and the stance, as I recall, was everyone just kinda waited to see how the world treated him. This is not a disparagement of any of my colleagues. I think we didn't understand how to react to this. And then the decision was quickly made at large that he had done a bad thing. And that's kinda the last we ever heard about him or those kids. The Chinese government condemned it publicly. Uh, I think they said he was gonna be punished, but it wasn't clear if he was gonna be punished by being put in a jail cell, being fined, or, um, given a larger laboratory and more resources. It was very unclear. It's playing God-

    10. AM

      Yeah

    11. AH

      ... at some level.

    12. AM

      Yeah.

    13. AH

      Right? It's not the same as deciding to not implant some embryos that were created through IVF because they carry an extra chromosome. It's different than that. It's taking healthy children, in this case, and making a change to try and make them, quote-unquote, super people. So I would love your thoughts on that particular instance, your, uh, awareness, if any, that, um, CRISPR in, in otherwise healthy humans has continued, and where you think this is all going.

    14. AM

      Yeah, I think you capture a lot of that moment. Uh, I, I wasn't there, but there was a international CRISPR conference that was being held, I believe, in Hong Kong at the time, and the, the scientist, um, got up and announced with inc- extraordinary pride in, in, in one of these sessions in this conference that he had done it. He had done genetic modification of embryos. And my understanding of what, what had happened was that there were two twins, um, who were, w- there, there was, were parents who wanted to have kids, and the father was HIV positive. And the modifications that they decided to try to make were to delete a gene that is, if it, if it's deleted, can confer resistance to HIV.

    15. AH

      Hmm.

    16. AM

      This is a gene called CCR5. There's people who naturally have a certain mutation in this, a certain, at some frequency, and mutations in this gene confer resistance to HIV if they're naturally occurring. So that was the supposed rationale.

    17. AH

      So there was a disease, um, aspect to it. Okay. I wasn't aware of that. Thank you for that clarification.

    18. AM

      It was, it was a prophylaxis against-

    19. AH

      Mm-hmm

    20. AM

      ... this potential risk of HIV. Now, there were a lot of troublesome features from what I understand. First of all, there's state-of-the-art methods to reduce the risk of HIV if through sperm washing and things that can be done that would, uh, from my understanding, essentially reduce the risk to near zero of transmission th- through, th- from a father to an embryo. So I think it was a bit of a manufactured need, but there was the suppo- supposed justification. Second of all, it was done, um, so they actually ended up generating two twins, and my understanding of how it was done, and I don't think that this was ever published. There was some, some publicity that was released, so I'm sort of piecing this together from what was, uh, public at that time. But I don't think any journal ever published this in a, in a peer-reviewed context. Um, they did this in concert with essentially IVF techniques, so they were fertilizing embryos with this, with this father's, uh, sperm. There's the mother's, the mother's eggs. They created multiple embryos, and then they delivered CRISPR into these embryos and trying to create mutations in the CCR5 gene. There was some variability. It was pretty early in days of CRISPR, and as I said, there's an unpredictability of what happens when you make a double-stranded break in the genome. So it was a stretch to say, okay, th- they didn't exactly get the mutations that they wanted, but they proceeded nonetheless to implant these embryos. And I know less about this, but there were also serious concerns about the way that consent was done on this. So, like, w- how much was informed about the a- what the actual benefits would be to these patients. My understanding is that he got up, and I wasn't in the room, but I do think that there was some degree of, uh, uh, immediate horror that this was being announced and that, that it was unfolding in this way and that it hadn't been considered. It, it was, it was not ready. In the wake of that, the Chinese government then announced that they were gonna punish this, and I don't know the details, but I believe that he unders-- uh, underwent some period of house arrest.

    21. AH

      Okay. He do-- He was punished.

    22. AM

      I, I believe so. After... I, I think after there was some degree of scientific outrage a- at this conference.

    23. AH

      Yeah, there was this pause moment that lasted maybe a week or two.

    24. AM

      Yeah.

    25. AH

      Um, okay. Well, you're clarifying a lot of the, the detail-

    26. AM

      And, and, and, but-

    27. AH

      ... important details.

    28. AM

      But my understandingAgain, is that he's now free, and I think is, is restarting a lab. I don't think in China, I think somewhere else. Um, so the story might not be over yet.

    29. AH

      Mm-hmm.

    30. AM

      So th-that's my understanding of, of the facts.

  25. 2:05:42 – 2:10:44

    Deep Sequencing Embryos, Diversity; Overcoming Adversity & Resilience

    1. AM

      o-offspring.

    2. AH

      Appreciate the clear stance and, and answer. Uh, as long as we're there, I'd love your thoughts on some of the newer technologies, uh, that are only available to those that can afford them-

    3. AM

      Yeah

    4. AH

      ... so that's an important caveat, for deep sequencing embryos from IVF.

    5. AM

      Yeah.

    6. AH

      So typically with IVF-

    7. AM

      Yeah

    8. AH

      ... check to see that they're chromosomally normal-

    9. AM

      Yeah

    10. AH

      ... that they're euploid, as they say, and they'll do some sequencing in the, of the parents, uh, maybe of the, of the embryos as well for certain mutations. But there's this whole other, um, industry now.

    11. AM

      Yeah.

    12. AH

      I believe a, a company in the Bay Area, Orchid-

    13. AM

      Yeah

    14. AH

      ... um, is, is probably the most popular, uh-

    15. AM

      Yeah

    16. AH

      ... one or well-known one, uh, where if you pay a certain amount of money, they'll, um, deep sequence. If you pay more, they'll deeper sequence.

    17. AM

      Yeah.

    18. AH

      Um, and so you're getting some additional readout of potential disease genes, and, and I-I've looked at that technology, and they're very clear that they're, at some point, they can't draw a causal relationship between, say, like a neuroligin mutation and autism.

    19. AM

      Yeah.

    20. AH

      But there are these implications based on the animal data. Or, uh, a-and so it, it starts to become this, it's not gene editing-

    21. AM

      Yeah

    22. AH

      ... but it is a deeper and deeper, uh, gene sequencing based selection of embryos.

    23. AM

      Yeah. First of all, I'm, I'm, I'm sympathetic to the idea, right? Like, we, we, we wanna protect our kids from, from, from suffering and from disease, right? And I understand the do-- idea of doing pre-implantation genetic testing if you wanna avoid a mutation or a chromosomal abnormality that would really impair lifespan or quality of life for your offspring. I, the impu-impulse that we know that's this, this sort of straightforward chromosomal testing that's done at, from, uh, the first level sh- does, will miss a lot of mutations. So people, I understand the idea of trying to fill that in with more deep sequencing or comprehensive sequencing of the genome. The problem is there are some mutations that if we know, if we see them, we will know that they can be, cause severe disease. But there's a lot that are become probabilistic and statistical, and I think we're overpromising what can be delivered.

    24. AH

      Mm-hmm.

    25. AM

      So all of a sudden, you're using an algorithm to determine which embryos are more desirable than others, and I think the fact is that it's just a, it's, it's not an axis that actually exists. There aren'tCategorically more desirable or less desirable, that we want diverse, diverse people for, for, and the, you know, how successful you're gonna be is a interplay of, like, how your genes inter-come around and influence your community, your, your environment. Those are unknowable from just looking at a DNA sequence alone. So I think that there's... it introduces a false axis.

    26. AH

      Mm-hmm.

    27. AM

      There's another book that I, I would, would recommend here that I read years ago, and I actually am probably overdue to go back and, and reread this. This predates CRISPR technology, but the, there's a Harvard philosopher, Michael Sandel, who years ago wrote a short book called The Case Against Perfection, and it's a really beautiful meditation on what's lost when we enter into this illusion of thinking that we can engineer towards some axis of perfection rather than embracing the beauty of chance, chance and happenstance, which is, like, a part of our relationship with, with our kids, with ourselves, of thinking, uh, okay, this is, this is the human experience of you're a product of some degree of chance and, and circumstance.

    28. AH

      I'll definitely check out the book. Um, I, I know the whole point of life is not to be a, quote-unquote, "high performer," but I, I'll just say as an example, um, I know of no single very successful person that doesn't have some thing about themselves that, um, that initially they disliked or felt that they had to overcome, which led them to pursue certain things, hopefully in a healthy way, um, and that they eventually came to embrace and is now, and are now grateful for. I, I know of no exception to that.

    29. AM

      Yeah.

    30. AH

      It's just kind of... It, it's of the story of, of humans in many ways. It's a story of humans. In fact, uh, uh, people who perhaps are told that they're perfect in every dimension their entire lives, um, they, I can only imagine the amount of pressure they must feel. In fact, before today's discussion, we were talking about people that we knew that perhaps had been told that and some of the, uh, fragility that that can introduce to the psyche.

  26. 2:10:44 – 2:17:55

    Upcoming Therapeutics, Autoimmunity & CAR T-Cells, CRISPR & Gene Function

    1. AH

      more. I'd love to know what right now you're most excited about for your own intellectual enrichment and in your lab and, and, like, what you really feel is, like, the, the thing that has the most electricity for you and, and if you're willing to also give us a hint of what's just right over the edge in terms of what you think will be the next big therapeutic breakthrough, um, that we can look forward to.

    2. AM

      Thanks for asking that. So I'm gonna give a little bit of a long-

    3. AH

      Please

    4. AM

      ... and meandering answer that-

    5. AH

      I mean, l-listen, when it comes to me, you don't have to...

    6. AM

      [laughs]

    7. AH

      Uh, succinct is not something that, sort of, is, or, like, exists in my neural circuitry, although I try.

    8. AM

      So I see this, this moment, I talked about clinical trials where... that are already filling me with hope. I talked about a, a, a biotech, uh, trial that I'm a-associated with for prostate cancer. I talked about an academic trial that I've put a lot of work in with my colleagues over many years to open for multiple myeloma, and we have a pipeline that we're developing. We didn't even talk today about, we, we, we haven't fully talked yet about the idea of CAR T cells for autoimmunity. We left that open a little bit, but that's an amazing moment that we're at right now, that the same CAR T cells that are being used to get rid of B cell leukemias are also getting rid of B cells which are contributing to autoimmune disease. So without making any change, people are already starting to see incredible responses in the early trials for lupus and other autoimmune diseases with T cells engineered to eliminate B cells.

    9. AH

      Oh, fantastic. Could you just mention a few other disease targets? I, I know a few people with fibromyalgia.

    10. AM

      Yeah.

    11. AH

      Um, they suffer tremendously.

    12. AM

      Yeah. Fibromyalgia is a disease that we just don't understand.

    13. AH

      Mm.

    14. AM

      Like, that is, that is... T-talk about understudied diseases, I think fibromyalgia is something that w-gets bucketed in a certain way, and we just have not figured out what, what is, what it really is, what, what causes it.

    15. AH

      Yeah.

    16. AM

      And so my... That, that is its own thing. But for autoimmune diseases, these are diseases where we do know that there are immune cells going after our own tissue in various ways. Lupus, people are th-talking about various engineered T-cell trials for rheumatoid arthritis, for childhood diabetes, for multiple sclerosis, um, and on and on. Uh, but those are a number that, uh, people are thinking about different types of immunotherapies, including gen-gene and edited T cells to treat these autoimmune diseases. So I'm already, I guess w-what I'm saying is, excited about the near future-

    17. AH

      Mm-hmm

    18. AM

      ... of things that have come out of decades of lab work from m-labs around the world already starting to be assembled into things that are advancing through clinical pipelines. But the next wave of what's coming up behind that is just as exciting, if not more. So I think that one of the things that makes me feel like I, I have one of the great jobs out there is I, I-- there's about 30 people in my lab. I get the joy of m-ideas bubbling up. They don't-- The ideas in the lab don't come top-down from me. They come from grad students and postdocs who have come filled with energy to bring their own ideas, and progress is being made through this conversation of people in the lab reading papers, going to conferences, talking late at night in the lab. AndI can't believe the surprises that are g-- that are coming. So I'll g-- I want to give you a couple of these. So I just look, looking backwards to two thousand thirteen, two thousand fourteen, we were struggling to see if we could get CRISPR into with electroporation to make one cut in a T cell. We could barely do it. Now, if a grad student comes into my lab, within a month or two, they can routinely do a CRISPR experiment where we do CRISPR, where we deliver a set of thousands, up to tens of thousands or hundreds of thousands of different CRISPRs into a population of T cells from a blood sample. So each cell will get a different CRISPR modification, and then we can essentially race these cells against each other. So we can put them into a tumor environment and see which ones continue to grow, which ones have markers that seem like they're going to be favorable in giving them characteristics that are going to be strong against cancer. So we are able to do the, the type of genetics that was possible in fruit flies, but unimaginable in human cells, we're doing directly in the human cells that will be the therapies of the future. We're directly learning what are the genetic modifications that will make T cells do exactly what we want. And one of the things that we just made publicly available is that we used to do these experiments and race these cells against each other and s-breed it, see, race them against each other for one characteristic, which ones would start to make one cytokine. I t-talked about these signals that immune cells can make. Now what we can do is we can, for each genetic modification, we can do a complete measurement of the state of each individual cell. W-we-- this is a technology called single-cell RNA sequencing. So we measure now simultaneously all of the, the RNA that's in that cell telling us, giving us a snapshot of what that cell is now able to do. And we can also simultaneously measure which CRISPR was put into that cell. And so now we can essentially inactivate every gene in the genome in T cells and read out the consequences on the overall state of the cells. And this is technology that was developed by a number of labs around the world. We've now deployed this a-at a massive scale directly in primary human immune cells. We just released twenty-two million cells where each one has a different CRISPR gene inactivated, and we get a map of this. And I think of this, not just what we're doing in T cells, but what other labs are doing around the world using CRISPR to read out the consequence of every gene in different cell types and different conditions as a sequel to the Genome Project.

    19. AH

      Mm-hmm.

    20. AM

      You know, we talked about the genome giving us this draft of the DNA sequence. Now we can actually read out the function of every gene and see how each gene contributes to the behavior of every cell. And this is being used with a, in t-- as a basis for massive computational analysis. It's providing us a, a real roadmap of how cells are wired that will be the instruction manual for the next generation of T cell immunotherapies. The, the lessons that we learn about how every gene behaves are now gonna be actionable, and these are gonna be genes that we tune or epigenetically edit or inactivate or add to genes that we will now have a recipe book for w-what, what do we want an immune cell to do? What do we want it to recognize? What do we-- where do we want it to go? And we'll have a cheat sheet-

    21. AH

      Mm-hmm

    22. AM

      ...that tells us, "Okay, here's what, here's what we should be adding or subtracting from that cell genetically to endow it with the powers that will give it precision and endurance against some disease that we wanna go after."

  27. 2:17:55 – 2:24:41

    Banking T Cells or iPSCs?, Future of Cell Programming

    1. AH

      Amazing. I mean, truly amazing. Um, should I be banking T cells?

    2. AM

      Well, I think the good news is that... That's a g-- I, I never know what the answer is to this. Y-y-- I was gonna say the good news is that we largely have T cells. Now, there are w-- Are there exceptions to that? Yes. You know, there are patients who are getting treated for certain types of cancer, and the, the chemotherapy that they're getting depletes their T cells. I-- It's hard to know. You know, you know, I guess I, I can't say that there would never be a use, but I think we're getting better and better at being able to take whatever T cells are there and, and-

    3. AH

      Mm-hmm

    4. AM

      ...I hope reactivate them, reendow them with powers. I would be disappointed if in the future we would need to go back and take the bank T cells and not be able to reengineer cells that are already there.

    5. AH

      Mm-hmm.

    6. AM

      Are there edge cases where it might be? But it's not something that I would tell people to go out and do.

    7. AH

      Mm-hmm.

    8. AM

      I- It's not something I'm doing.

    9. AH

      I-- Yeah, I would only do it if you told me to. Uh, a colleague of yours, um, Yamanaka-

    10. AM

      Yeah

    11. AH

      ...won a Nobel Prize-

    12. AM

      Yeah, yeah

    13. AH

      ...for, uh, essentially showing that you can take a skin cell, put it in a dish, give it Yamanaka factors-

    14. AM

      Yeah

    15. AH

      ...as it were, for in some cases only three transcription factors-

    16. AM

      Yeah

    17. AH

      ...and essentially revert that cell to a stem cell.

    18. AM

      Yeah.

    19. AH

      And then give it some other transcription factors and turn it into, I don't know, a neuron or a pancreatic cell. Should we be banking fibroblasts and putting them into that ready state, um, reverting them to the stem cell state? I, I-- In my mind, I always thought, well, if I ever need more cells of a given organ, I can always, assuming I'm, I'm alive, they-

    20. AM

      Yeah

    21. AH

      ...you know, they can take a skin cell, and they can do all that. But I could imagine that there would be use for a cell bank, not a tissue bank, where there are a bunch of these pluripotent-

    22. AM

      Yeah

    23. AH

      ...Huberman in my case, Marson in your case, obviously, uh, cells that if, uh, you know, God forbid, I needed a bunch of pancreatic islet cells, boom-

    24. AM

      Yeah

    25. AH

      ...they could have those within a week.

    26. AM

      This field is s- is something that's been amazing to watch. It, it's-- There's been ups and downs of it, of this induced pluripotent stem cell field that Shinya Yamanaka opened up. Um-One of the interesting areas is actually imagining how these iPS cells could be made into T cells, which would essentially create a limitless supply of T cells.

    27. AH

      That's what I was thinking.

    28. AM

      Yeah.

    29. AH

      You know, you don't have to even draw blood.

    30. AM

      Exactly. Which would negate the need for banking if you had your... So I don't know if, again, it's probably not something that I would be cost-effective for everyone to have their, their iPS cells are ready to go. I understand from, in conversation from, from Sh- with Shinya Yamanaka that one of the things that he has been involved with is actually building sort of a bank of iPS cells that would be compatible, immune compatible with broad sets of different people so that it could essentially be used as a transplant bank-

  28. 2:24:41 – 2:27:12

    Zero-Cost Support, YouTube, Spotify & Apple Follow, Reviews & Feedback, Sponsors, Protocols Book, Social Media, Neural Network Newsletter

    1. AH

      again.

    2. AM

      Thanks.

    3. AH

      Thank you for joining me for today's discussion with Dr. Alex Marson. To learn more about his work, please see the links in the show note captions. If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. In addition, please follow the podcast by clicking the follow button on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review. And you can now leave us comments at both Spotify and Apple. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. If you have questions for me or comments about the podcast or guests or topics that you'd like me to consider for the Huberman Lab podcast, please put those in the comments section on YouTube. I do read all the comments. For those of you that haven't heard, I have a new book coming out. It's my very first book. It's entitled Protocols: An Operating Manual for the Human Body. This is a book that I've been working on for more than five years, and that's based on more than thirty years of research and experience. And it covers protocols for everything from sleep to exercise to stress control, protocols related to focus and motivation. And of course, I provide the scientific substantiation for the protocols that are included. The book is now available by presale at protocolsbook.com. There you can find links to various vendors. You can pick the one that you like best. Again, the book is called Protocols: An Operating Manual for the Human Body. And if you're not already following me on social media, I am Huberman Lab on all social media platforms. So that's Instagram, X, Threads, Facebook, and LinkedIn. And on all those platforms, I discuss science and science-related tools, some of which overlaps with the content of the Huberman Lab podcast, but much of which is distinct from the information on the Huberman Lab podcast. Again, it's Huberman Lab on all social media platforms. And if you haven't already subscribed to our Neural Network Newsletter, the Neural Network Newsletter is a zero-cost monthly newsletter that includes podcast summaries as well as what we call protocols in the form of one to three-page PDFs that cover everything from how to optimize your sleep, how to optimize dopamine, deliberate cold exposure. We have a foundational fitness protocol that covers cardiovascular training and resistance training. All of that is available completely zero cost. You simply go to hubermanlab.com, go to the Menu tab in the top right corner, scroll down to Newsletter, and enter your email. And I should emphasize that we do not share your email with anybody. Thank you once again for joining me for today's discussion with Dr. Alex Marson. And last but certainly not least, thank you for your interest in science. [outro music]

Episode duration: 2:27:12

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