Avoiding, Treating & Curing Cancer With the Immune System | Dr. Alex Marson

We're living in this amazing moment of biology where we can put a gene that encodes something on the surface of T cells that will make them programmed to search and destroy for cancer cells. 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 blood transfusion, those cars are directed to go against cancers.

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Welcome to the Huberman Lab podcast where we discuss science and science based tools for everyday life.

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I'm Andrew Huberman and I'm a professor

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of neurobiology and Ophthalmology at Stanford School of Medicine.

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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

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probability of getting cancer.

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In addition to the usual factors, smoking, UV light and environmental toxins such as pesticides, we discuss the actual cancer risks that come from things like eating charred meats, airport scanners and food additives, and how to gauge your individual level of risk. We also explore gene editing for reversing diseases, which until recently was science fiction but now is a reality. By the end of today's episode, thanks to Dr. Marson, you'll have the most up to date understanding of the state of the art science for cancer prevention and treatment. Knowledge that is certain to impact you or a close friend or family member in your lifetime. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Alex Marson.

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Dr. Alex Marson, welcome Andrew. This is the first time that we're going to have a serious discussion about the immune system, cancer and gene editing technologies on this podcast. So I'm delighted that you're here it's also great to see you again.

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

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It's been a while. Let's start off with the big picture. How are we doing? How's biology looking? How's medicine looking? Are we, are we on the fast track to much better things? Are we going to slog along for another 10 years before we have cures to the many concerns that people have about cancer, Alzheimer's and the rest? Or are you encouraged by what's happening right now?

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I think maybe there's some. The general public doesn't quite know how excited biologists are about what's possible. And maybe we've over promised, 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 at the root causes of disease. And over the course of this conversation, I imagine we're going to talk about DNA sequencing, understanding cells, but going all the way to rewriting specific DNA sequences inside of the cells of our immune system. Doing this not one at a time, but test every gene and understanding pieces of DNA throughout our entire genome to understand what controls our cells and then being able to take that information and actually do something about it, to boost our immune system to go after cancer, to balance it for inflammation and autoimmunity. And that doesn't just have to be sort of searching for a pill. All of a sudden we can actually talk to our own cells and give them instructions in the language of DNA and the language of molecular biology. And in some instances this is being done with 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. There's really a step function in what's imaginable and achievable in medicine.

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

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Yes, is the answer all of those things? I think we can do experiments at a different level of scale. We can generate data and then we have the computational tools, including AI, but we have computational sophistication to actually extract insights from massive amounts of data. And I think historically biology was it Was an observational science. Especially if you wanted to study things in humans, There wasn't a way to intervene. Now, all of a sudden, we're taking human cells, we're taking them into the lab and making genetic changes and reading out the consequences and directly being able to observe the effect. And 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 consequences when we actually go after targeted DNA sequences and make our cells better at treating disease.

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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 other things.

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Today, our immune system permeates almost every aspect of our health and disease. It is a system really, in the sense of 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, 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 its core, that's the basic job of the immune system, to

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recognize us versus non us.

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Exactly. And you talked about the innate versus the adaptive immune system. Largely, what we're talking about are white blood cells. We're talking about different types of white blood cells that are either inside of tissues or circulating in our bloodstream that go around and play coordinated and specialized roles in sensing. When something comes in that is not us, that's foreign, that shouldn't be there, the innate immune system does. It is sort of thought of as the first alarm system that something's wrong. And with the innate immune system, which consists of 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 generic way in a healthy human. When those first alarm systems get triggered, all of a sudden these innate immune systems start releasing things. They change their state, and they send off an alarm to other cells in the immune system, and then they often recruit in the second arm of the immune system that you mentioned, the adaptive immune system. We'll talk a lot about the adaptive immune system today. And the major players in the adaptive immune system are a group of white blood cells that are collectively known as lymphocytes. But we'll talk about B cells and T cells in particular, which are major groups of lymphocytes. We've been focused heavily on T cells. T cells play a central role in coordinating the fine tuning of the immune response. One of the amazing things about T cells is that each T cell naturally in our body, is one of the few places where each cell will actually have a different piece of DNA that's not inherited. 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 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 been recognized as foreign. And so we have this incredible diversity of different T cell receptors that have developed on our T cells. Each one will have a different unique receptor on its surface. Each cell will have a different receptor on its surface. And the way to think about these receptors is that they're sensors. When they're engaged, they send a signal to the T cell that, okay, we found something that you've been programmed to recognize and program is recognized as far in if the immune system is working properly.

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And are the genes that these T cells make as these receptors are those based on experience of the organism? Because you said that it doesn't come from the germline. But we should clarify that the germline is not about infectious germs. In this context, the germline DNA is from the sperm and egg that were your parents. It became you. There's recombination of those genes, and then there's you all. Each and all. 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?

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Largely random, Actually, there's the pieces of DNA at this part of the DNA actually recombine and get pasted together in unique ways.

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So it's probabilistic.

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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 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 on the surface that viruses would introduce.

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That's incredible. Would you mind mentioning the role of the thymus? These days I'm hearing more and more about we have a thymus and we lose a thymus. Would it be beneficial if we could keep our thymus around?

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So thymus is actually the reason the 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 sort of lies by your heart. And it is the place where T cells go in a key place of their education. So they are making these sensors largely at random. And in the thymus, they get cold, they get selected, and the ones that by accident are generated that recognize something that is supposed to be in your body. 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 emerged at random but then are selected to remove things that recognize your own body targets.

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There's sort of a negative selection. There's a negative selection of the st, that's you, so that your immune system doesn't attack you and it knows you from non you.

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

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Okay, so your thymus and your T cells get educated in childhood and that's what you're working with. Except that the immune system can adapt and make antibodies to things it doesn't recognize.

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The antibodies come from the other type of lymphocytes. So 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 through a similar kind of recombination event. They have their own form of selection that they go through. And then those antibodies can then be released into the bloodstream and are the basis for protection against infections after we get them.

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What underlies the sort of efficiency and functioning of the immune system? I know I and many people are thinking, okay, we hear like our immune system gets activated or our, our immune system is impaired. The one thing that I'm certain supports the immune system is great sleep, right? We just know this. If we don't sleep well or enough, we get sick. Is that because there's a known impairment of the immune system.

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I wonder about this too. I mean I agree anecdotally I've experienced that so many times of being run down and then experiencing that I'm susceptible to infection. But I don't actually know the basis of that. I mean it's kind of amazing how much we don't know about these determinants of immune health largely because they're often variables that are left out of the mouse studies that we're doing. We're studying largely steady state immune responses in mice and I would say we haven't done a full exploration yet of all the types of ways that general health impinges on the immune system. I had someone in my lab, a postdoc named Sagar Bhupat who came to my lab with an interest in metabolic health and wanted to study the effect of metabolic health on T cells. And there's some sub growing stuff on this, but it's another like what are the determinants of it? He did experiments in my lab where he exposed an allergen, something that irritated the skin and caused an allergic type reaction in the skin of mice. He did it in mice that were eating a normal mouse diet versus a high fat diet that caused obesity. And what we saw was that it was actually not just a quantitative difference in the immune system, but actually a qualitative difference. The actual type of inflammation, the cell responses were different in the mice eating a high fat. And I think we haven't done enough studies like that where we Actually start playing with the variables of life and test them in a mechanistic way to isolate individual variants. What was interesting there was that the allergic reaction actually looked totally different in the obese mice. And if we used surrogates 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. They didn't help the mice that had the obese high fat diet response to inflammation. And in some cases it actually maybe made it worse. Interesting. So I think that there are these systemic ways. I mean, clearly our intuition tells us this strongly that systemic health can feed into our immune responses. But I think it's still been under explored in rigorous ways.

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I realize I'm asking very top contour type questions for which there probably aren't specific answers, but we all know people that get sick all the time and we know people who never seem to catch the bugs that everyone else seems to catch. Is there any understanding of what a more robust immune system is at the level is it more T cells, Is it. Are the B cells engaged more quickly so they can generate antibodies more quickly? What is it?

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Great questions that I don't think have full answers. There's been a lot of work on genetic determinants. And there's extreme cases where people have a genetic gap in their immune system where they're really susceptible to something that healthy people should not be susceptible to. And you see that there are certain types of infections that either happen or happen with a different type of severity in people with genetic deficits in certain branches of their immune system. 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 response is and the consequences that manifests itself with different types of infection. And I suspect that there's some spectrum of that we see you can diagnose the really strong genetic consequences. And then there might be a long tail of more subtle genetic that might be multigenic that we don't fully understand. And then I'm sure that there's other determinants of health that are just multifactorial. It also becomes this interplay between the health and then what you get exposed to by your environment.

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Yeah.

20:57

Speaking of which, I'm familiar with some studies from Stanford, I believe, where kids that have no exposure to peanuts get peanut allergies. And careful, subtle increasing exposure to peanuts essentially protects them against peanut allergies so is it true that when we're young that exposure to pathogens and different foods gives us a more robust immune system?

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I think that what we're exposed to and what we develop tolerance for is critically important. During there's some windows of early life that I think we're particularly susceptible to becoming tolerant. And I think if we don't get the proper exposure to certain things, all of a sudden our 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 hesitant to expose kids. And I think it can get into these dangerous. You don't want to expose kids who are going to have a dangerous allergic response. But on the other hand, critical early exposure is part of how tolerance is maintained. And I think peanut allergies. There is strong evidence that exposure to peanuts can be beneficial in people who are not yet allergic.

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What's going on with autoimmune conditions? Yeah, is this that the B cells and T cells are at a probabilistic level. The T cells developed some reaction, so to speak, a binding to cells that we naturally make that they shouldn't have. It was just like it happens. I've always been intrigued by the idea that when the immune system is really ramped up, people will experience autoimmune like symptoms. I experienced that as a master's student. I was working so much and probably not eating enough and drinking so much caffeine back then that I got some kind of funky skin lesion things. I went to the doctor. Oh, you're starting to get some attack of the deeper layers of your skin. You just need to work a little less. And sure enough, did. That did the trick. It did the trick, but it made me so keenly aware of how the immune system will, for lack of a better word, adapt to conditions. And it was trying to keep me healthy and it overshot the mark. Basically.

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I sort of walked you through at a first principle, how things are supposed to work. I told you, okay. There's this process of generating receptors on the surface of T cells. Antibodies get generated on B cells. They go through this positive selection and negative selection. That's a delicate balancing act. And it doesn't actually work that way in practice. In practice, T cells escape from the thymus that do recognize our own self antigens, and there's actually secondary mechanisms to block that. But autoimmune diseases emerge when those normal checks fail. And I think it's a consequence that the Immune system has two major responsibilities. It has to be primed to protect us from infections which would be fatal and be strong and recognize this incredible diversity of potential foreign dangerous things that we might experience. But it also has to not recognize our own cells. And it can miss the mark in both ways. And so autoimmune disease manifests in different tissues. If your immune system starts recognizing targets, if it's in your joints, it can cause rheumatoid arthritis. If it's in the cells that produce insulin in the pancreas, it causes type 1 or childhood diabetes. If it's the myelinated cells in the brain, it's multiple sclerosis. So this is autoimmunity and inflammation of different kinds cause their own pathology. So we want to. The immune system is always these sort of two sides of the coin, making sure that we're having strong responses to infection. We'll talk about cancer, where we want to also strengthen our responses. But for autoimmunity, inflammation, allergies, we want to make sure that our goal therapeutically with drugs, is to make sure that we make the immune system under control and ideally do it in a targeted way so that you don't have to turn off the whole immune system with blanket immunosuppression, but to do it in a way that just makes you tolerant or not reactive against the things that are being inappropriately targeted by the immune system.

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Two things that I'd love to understand about the immune system is how is it that an immune response, let's say, to a cold virus, is systemic? Where is the sort of master controller, or maybe it's a distributed system that says, okay, we need to launch a body wide response as opposed to a localized response. I can imagine, like with a splinter. Of course you're going to get a localized response. It's a little piece of wood or metal. And so you're gonna get the innate response and you're gonna get some pus around it and it'll kind of localize the wound. But when it comes to an invasive virus, like the cold virus, it overtakes us, right? The production of mucus, we get a headache. And I think it's the systemic effect that intrigues me so much. Like, where is the signal to launch a systemic versus a localized response in the immune system? How does it determine that?

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You know, I think some of it depends on what virus we're talking about, how systemically invasive different viruses can be. And some of it can be that the immune system has different levels of, you know, it can have a local response. But the immune system, the cells that we talked about in the immune system, one of their jobs can actually be to secrete things into the bloodstream. Things that are essentially chemical signals that something is wrong. Major ones are, they're called cytokines. And they can act locally, but they can also have more distributed effects. And some of the things that the cytokines can do can influence, can cause the development of fever. So you can have these sort of cascading effects of something being recognized at a particular site of the body, then sending distributed signals to the blood that will make us feel sick. And in some cases, there's again this balancing act of maybe the fever gives us some edge in fighting some types of infection, but it also makes us feel lousy. And so the immune system is always walking. I think sometimes the immune system response to infections is too strong. And a lot of the negative consequences of what we experience is the immune system going too far and having to come back as an infection gets under control.

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Thank you. One of the reasons I ask that is, well, I hate being sick. Fortunately, I don't get sick too often if I take good care, which I think is like most people. I think about antibiotics, for instance. Antibiotics are amazing. I've had a few things where I was like, oh, this thing's bothering me. And 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 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 and you can end up with antibiotic resistant infections. That's a concern for sure. But what is the sort of inherent danger of using things like antibiotics the way I described, like, not in a, in a life or death situation to mitigate the duration or the intensity of some sort of infection? Because surely you're short circuiting your immune system's ability to eventually just fight that thing off. Like, is part of building a robust immune system across your lifespan, Allowing your immune system to do the work and going through the misery of being really sick and infected?

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I don't think so.

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Great.

28:57

Okay, fantastic.

28:57

Love that answer.

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Love that answer.

29:00

I think you probably were exposed and had an immune response. Antibiotics, when they're used for bacterial infections that are susceptible to them, are a miracle. And we Live in this amazing sliver of human history where we have antibiotics that can cure disease. I mean, I think many of us have had bacterial infections of different kinds, cuts and wounds that would have been deadly in other generations. And we're the beneficiaries of having antibiotics that work. We are at some risk that if we overuse them, that window of human history might come to an end if we don't continue to replenish new antibiotics, but we gain more and more bacteria that are resistant to antibiotics.

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Are people developing new antibiotics?

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It's an underfunded area of medicine because

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I just hear amoxicillin, penicillin. I have a friend over in the UK who's been having some eye symptoms that from what I'm learning, we're still learning, is likely an infection near the posterior chamber, which just simply means his vision is potentially at risk. Systemic antibiotics are very likely going to save his vision. And so people say, well, antibiotics are bad. 100 years ago, he probably would have just. They would have just enucleated the eye, which is to be blind. Right? So I think they're a spectacularly good tool. But it seems like there's just a kit of maybe what, five to a dozen very commonly prescribed ones. Why aren't people developing better, newer, new generation antibiotics? Seems like it would be, if for no other reason, a trillion dollar industry, but also save a lot of lives.

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I don't know whether there's a business reason for that, but it is an underfunded area. It's not where medicine is, has turned enough attention, and I do think it's a genuine risk.

30:34

All right, well, some entrepreneurial young guy or gal, or both will launch into it. I want to understand the relationship between the immune system and cancer, but perhaps first we should talk about cancer, what it is and what it isn't. I think there's a lot of misunderstanding out there that cancer did not exist in 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?

30:45

Yeah, yeah. I mean, if anyone's really interested, I would highly recommend this book, the Emperor of All Maladies, which is a, which is really a biography of cancer as a disease. And talk about, I mean, the long history of going back as far as there's records of tumors of various kinds and the misery associated with that. We have A very different understanding of cancer right now. Right. And I think cancer is one of the most sophisticated. Where we have one of the most sophisticated genetic understandings of disease doesn't mean we can always do things about it. But now we can understand mutations that accumulate in 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 skin cell in cancer, all of a sudden, some combination of mutations emerge in that cell that lose its normal regulation. The skin cell is no longer getting the proper signals from its DNA to stay in the right place. And it goes and switches into a mode where it's dividing out of control. And the result is that those cells will then transform into cancer cells. They'll start dividing, they'll lose the normal architecture. The risk is that they can disrupt things in the 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 a cancer goes from one local site to another part of the body. And as that happens, those cancerous cells, 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 growing at the expense of the normal coordination of the human body. And that's really at its core what cancer is. It's genetic disease where cells lose the normal regulation and are dividing out of control in various tissues.

31:22

I can see the picture in my mind where otherwise healthy cell gets a mutation. We can talk about how mutations arise and then starts spitting off daughter cells, as it's referred to. Why would the daughter cells inherit the mutation necessarily to then create more cells? Because that's the proliferation of the tumor.

33:30

Yeah.

33:51

Certainly cells propagate their DNA into their daughter cells. But 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 terminal, as we say. Right. And they don't create more cells. Is that happening all over the body every day? So how is it that the DNA that creates the further propagation gets passed from one cell to the next?

33:51

I do think this is happening constantly. It's a process that every time a cell is around, especially as it's dividing, there is some imperfection in how the DNA, the DNA has inside each of our cells, if that cell is going to replicate, the DNA has to replicate itself. So you end up with two copies of DNA that should be the same, each one being passed on to the two daughter cells of that dividing cell. That process of DNA replication is imperfect. And if there's any kind of damage during that process, one of those two copies might end up different than the other one, in which case you end up with a mutation. Now, in one daughter cell and not the other, if that is deleterious or if it's damaging, which probably most mutations are, those cells might start to die off. Okay, the DNA got messed up. Those cells that are carrying that DNA,

34:21

yeah, they can't take up glucose. They just can't do cell stuff.

35:13

And there's a lot of control mechanisms in the cell that say, something's wrong. Let's send a programmed cell death signal to that cell. And cells will kind of implode with various processes when something is wrong. And that happens most of the time. The problem is if that change all of a sudden starts to not be damaging, but to actually be a signal. Okay, now the cell is growing more. It has some benefit that it's accumulated as a result of that mutation. Now that cell will start to divide more, and that cell that's carrying that first mutation might start dividing more. Both of its daughters now will pass on this mutation that's made it divide more. And if in subsequent rounds, it gets a second hit, the combination may go from just cells that are dividing a little bit more to cells that take off and become full blown cancer. Now, there's certain processes that would accelerate that. One was exposure to things that cause DNA damage. The major one is smoking. When smoking causes chemicals to go into your lungs, the lung cells get exposed to these chemicals that then cause higher amounts of DNA damage, more mutations. And just as you have more mutations at a higher frequency, you're more likely to accumulate a set of mutations that will gradually go on to cause the generation of cancer. Another way that this process can be accelerated is that some people carry an underlying genetic predisposition to cancer. So people will likely have heard of the BRCA or the BRCA genes which predispose to breast cancer and other types of cancer. There people start with one copy. That's already setting them on a road to higher risk of mutations accumulating. And the whole process happens with a higher frequency. And so this march towards cancer cells is more likely to occur in people with that type of predisposition.

35:17

How common is the BRCA mutation? Is it equally distributed in men and women? Yeah. What can you tell us? And should everyone get tested? For brca. And there's a lot of questions here. I'll ask them again one by one and then of course we'll talk about things that could be protective. Not just, but certainly avoiding smoking would be paramount.

37:19

So how common is breath in terms of mutagens? The big ones are smoking. Sun exposure for melanoma. I know the balancing features of sun exposure.

37:40

Yeah, we can talk about that.

37:50

But clearly UV is a risk factor for DNA damage in the skin.

37:52

I mean I'm perfectly happy going on record. The things I've said around sunlight have been contorted so many different ways. It's like a pretzel twist now. No, it's more like one of those balloon animals at a party. But it's not. It's a mess. The too much UV is bad for skin cells. It's just bad. You need some. But too much is bad. Long wavelength light is great. And therein lies the challenge. But yeah, love sunlight. But you don't want excessive uv.

37:58

Don't get.

38:22

But avoid getting sunburned, folks. Yeah. Thank you. So yeah, the BRCA mutation. I have a personal relationship to this because I lost both my graduate advisor and my postdoctoral advisor to BRCA mutation related cancers. 50 and just a little bit older than 60 and the other and brutal. Especially when you one of them. I know they're kids and just for young people getting cancer and I know they're childhood cancers. But BRCA seems pretty common.

38:23

I don't know the numbers off the top of my head. I mean they're not the major numerical causes of cancer. In the scheme of cancers that develops, 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 as an individual, your risk goes way, way up. And of certain types of cancer in particular.

38:54

And we can all get tested for it now, pretty cheaply, right?

39:23

Yes.

39:25

Yeah.

39:26

Yeah. That's certainly recommended if there's a family history of cancer for BRCA mutations and a couple of other ones. But you're right, the tests are available. And you asked about men and women. It actually was men were some of the ways that those BRCA genes were identified because it's so rare for men to 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.

39:26

Interesting. Everyone get tested for BRCA because there are lifestyle factors that can reduce your cancer risk. I'D like to talk about mutagens. Smoking bad. I'll go on record saying vaping bad. Perhaps not as bad as smoking, but still way, way worse than not vaping. The battle to sort of protective vaping as like beyond me. But okay. To each their own environmental sort of. And workplace hazards, you know, like known mutagens. If you work in a laboratory, you're working with mutagens. Right. You're working with things that literally pull DNA apart.

39:56

Yes.

40:37

It's always worried me working in a laboratory. There are a lot of carcinogenic chemicals

40:37

in a laboratory for good reason.

40:41

Right.

40:43

This is the. Yeah, we're trying to study cancer, but we're certainly working around a lot of things that could cause cancer. Chemicals, radiation. Yeah, I don't know about you. I did a lot of experiments. Radio labeling cells.

40:43

Yeah, I mean, well, fortunately we worked with radio tagged amino acids. With radiation. That was, we were told and I do believe was not as dangerous as some of the others. But yeah, I mean, so chemical exposures are a big one. And so those labels on paints and thinners and stuff in the garage, that's real. That's a real thing.

40:57

They make mutate cells and there's some spectrum of stronger and less strong ones. And I think oftentimes we're operating in an absence of great data. But I think there's a lot of things are implicated as potential mutagens, pesticides.

41:20

You look at cancer rates in rural areas near where crops are dusted with pesticides. And we've had Shauna Swan came on here and she's like, listen, the cancer risks, the endocrine disruptor risk, we think of as like big cities as dirty and dangerous. And they are for certain reasons. But she said if you really see the spikes in these cancers related to environmental factors, it's less so bus exhaust than it is pesticides.

41:35

I mean, it is not evenly or fairly distributed. Some people get exposed way more to these things and we haven't studied them enough. We need way more study to really be able to answer. Okay. And people shouldn't be left. This is me just speaking. It's kind of amazing to me how much we're left on our own to be figuring out what the risk of individual products is. And I think it's a place where we should be investing a lot more to get clarity on where the real risks are.

42:04

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42:34

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43:13

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43:14

I get X rays at the dentist now and again, but I prefer not to get them. X rays cause mutations.

43:58

Yeah, again, there's a. The trade off and the dose. You know, when you need an X ray, you need an X ray. But I wouldn't do them for fun.

44:04

Right. I mean, I have colleagues who prefer to do the slower manual pat down at the airport to going through the scanner. It's a low level of radiation is what they tell me. But if you're traveling a lot, you're getting multiple low levels exposures. And we know pilots, and this is for other reasons because you can tell us, but atmospherically they're exposed to more radiation. Cancer rates are higher in pilots now. They're sitting a lot too. Prostate kids. Okay, there's a bunch of things there. But do you yourself avoid the scanner at the airport?

44:12

Honestly, I do, but I can't say that there's data for that. I feel the same way as you like if I can avoid it. I try to minimize, but that's not based on some inside knowledge I have. But I have the same bias.

44:50

Sure.

45:03

Yeah. Less seems better.

45:03

Yeah. I mean, I'm not Out to get the scanner industry.

45:05

I think it's useful for people to

45:08

hear that that one can have no formal data, but an understanding of mechanism that leads them to hedge. Yeah, it's good to know are there any mutagens and.

45:10

Well, is a carcinogen and a mutagen the same thing?

45:23

So they're closely related. Mutagen I think means that you're mutating, that you're changing the DNA in the cell. That's the idea that those mutations may or may not be linked to cancer, but by virtue of the fact that you're causing more mutations, almost inevitably you're also increasing the risk of cancer. And carcinogens are things that increase the rate of cancer.

45:26

I love barbecued meat. I don't like barbecue sauce because it's sweet, but I like meat with a char.

45:48

Yeah, yeah.

45:53

Is the char bad?

45:54

I think so. I mean, I like it too, but yeah, again, these are balancing decisions in life.

45:55

Sure.

46:02

But yes, there's some. There is. I mean meat in general has been implicated as a potential carcinogen, especially in colorectal cancer. There's some data around that.

46:02

Yeah. My read of those data, not the char data, but the meat data is. It's tricky from this is just my standpoint. I want to make sure I put brackets around this, that this is my understand read of the literature is that many of the studies that looked at red meat rich diets versus plant based diets, the problem is a lot of times the red meat enriched diets had a bunch of other things in them, like sourcing wasn't considered. There was also a lot of starches because nowadays you find people who seem to at least feel better, who knows about the longevity aspect, but feel better eating red meat, fruits and vegetables, limited amounts of starches. So I feel like the nutrition studies are a mess. They're kind of a disaster.

46:12

I certainly don't have clarity on this and it seems like it changes the direction. I think some things we have pretty good common sense intuition about fiber. Yeah, ultra processed foods are probably bad, but I think the balance of exactly what whole foods we're eating probably still needs to be worked out.

46:58

How do you think about the data on like for instance, food dyes? This is very timely where a certain food dye at a very, very, very high concentration in laboratory animals creates a significantly higher incidence of tumors and cancers in those animals. But then the amount of food dye that's in the human food is a tiny fraction of that. I'm not trying to get political here. I just Think as a framework for people to think about. There are many carcinogens, I'm sure, Right. In this environment. I don't doubt that the lacquer on this table, in fact, if that's even what they used, if ingested, could cause cancer. I don't doubt that. Right. But I don't know that in its form here, being near it for many hours a day does that.

47:20

I doubt it.

48:07

We're not inhaling the table.

48:08

This is what I mean by this, this level of confusion. I think we all live with this background confusion of some study has been published in mice at high concentrations. Exposure doesn't mean anything in our lives. What's the relative risk? So that's why I start with smoking sunlight, and then say there's a tail. And I don't think we know fully what that distribution is yet. I'm sure there are some combination of things that are increasing our risk of cancer.

48:09

We don't really know how to weigh duration and amount of exposure. And this is why I think it's really scary to people. People don't know. They know smokers who don't get lung

48:36

cancer and non smokers who do and

48:46

non smokers who do. And so I think people go, well, like what it actually has caused, I believe a lot of damage in the faith in medicine, unfortunately, because the messaging is all is mixed up. Yeah. I think that nowadays people are trying to do what they can to protect themselves, but people still get cancer. You can do everything right and still get cancer, even if you don't have a BRCA mutation.

48:49

Absolutely. I mean, absolutely. You know, I think the last thing you ever want to do is like, attribute someone's actions to cancer. I mean, it is a probabilistic disease where some set of mutations occur that cause a really devastating disease. And so, yeah, I mean, we don't know the answers, and I think we have to be humble about that. Now what I think we can also talk about is, well, how do we handle. How do we treat cancer when it comes up? And this is where these two conversations that we've been having really come together. 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 2000, the dogma was, don't waste time thinking about cancer immunology. Cancer immunology is a field that's going nowhere I mean, I think I was in Boston. I think maybe there was some local bias in that direction, but this was not the mainstream of thinking about how we would treat cancer at that point. The way that cancer was being treated was chemotherapy, which is something that's been around for decades. And it's basically give toxins to the body that will be more toxic to the cancer cells than to the healthy cells, and ask people to endure all the side effects because they have to, to get rid of the cancer cells. And that's still the mainstay of cancer treatment. We all want to do better than that.

49:11

It's very unpleasant. Very, very unpleasant.

50:46

Unpleasant and worse. I mean. I mean, people endure heart. You know, it's. We put people through horrific things because it's the best we can do. And then there was a wave of thinking, okay, well, let's try to make drugs that are targeted to the mutations that we talked about. And that was the hot thing, that was the promising avenue when I was in medical school of like, okay, now we've really measured. These are mutations that accumulate inside of cancer cells. This is what's causing cancer. 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.

50:48

So these are cell cycle inhibitors signaling

51:29

various mutations affect these growth properties of cells. And there's targeted drugs that have been designed to go after some of those pathways that are making the cells divide out of control. I think that benefit has come. But cancer has ways of mutating around that and developing resistance the same way we talked about resistance in bacteria to antibiotics if they're exposed. Cancer cells can evolve quickly and can become resistant to these targeted modifications. What has emerged as a whole new way of thinking about going after cancer is using the power of the immune system that we talked about at the beginning and redirecting that against cancer targets. This has changed how we think about cancer treatment. The hope is that 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've talked about how they're really exquisitely evolved to make a determination of, this is a healthy cell. This is not a healthy cell. 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. Now, that is not science fiction. And is now approved and used to treat a number of different cancers. The first place where this happened was in a class of medicines called checkpoint inhibitors or immunotherapy drugs. A lot of people will have heard of these things. PD1, CTLA4 are some targets where there are drugs that get infused that hit these things that are on the surface of T cells and 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 brake on the T cells, the T cells go stronger and they can be unleashed against cancer just by taking the brakes off of them.

51:33

What sorts of cancers has it been successful for?

53:52

So the poster child for this has been melanoma. One of the big success cases was, was Jimmy Carter who had a melanoma, which is a skin cell aggressive skin cancer that had already gone to his brain, which was thought of as a death sentence. And he got treated with checkpoint inhibitors and basically was cured.

53:55

Amazing.

54:15

And so we saw these tumors just shrink away. And not just him, but in a large fraction of melanoma. Patients now respond to these. And so that has changed how melanoma is treated. It's and other cancers to varying degrees because some types of cancers can respond to this. That's taking a drug that unleashes the T cells that are already in our body. The focus of my research is. Well, the first thing I said was we're living in this amazing moment of biology where we can do things to cells in our body that with incredible precision. 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, the T cells that are naturally in our body that already have this random distribution of sensors. We can actually genetically make one of these sensors for T cells and put it into T cells. 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. Now this is largely known as chimeric antigen receptor T cells, that's 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 blood transfusion, those cars are directed to go against cancers. This has been done for certain types of leukemia and lymphoma, and there's been these amazing success stories. The thing that woke up me and the world was in 2012, there was a young girl who was the first pediatric patient to be treated with a car T cell for cancer. So she's become a heroic figure. Emily Whitehead. She was, I think, eight at the time, and she had a form of leukemia that hadn't responded. It just was. For some reason, Whatever reason, it failed all the treatments, and it just. Nothing worked. She was going to be sent home on hospice. She had exhausted all the possibilities at the age of 8, and she got enrolled in, 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 own T cells were genetically modified. And we could talk about how that was done. It was actually done with a pretty crude technique that's been around, actually used viruses, lentiviruses, these are sort of modified hiv viruses, to deliver this extra piece of DNA that encoded the car. This 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 ended up in the icu. The immune system had, in real time, people had to figure out how to control the immune system and the side effects. But as that was controlled, all of a sudden, her cancer cells disappeared.

54:16

Amazing. And the lentivirus itself didn't spark an immune reaction that was. That outweighed the benefits of the cargo.

57:44

No, amazingly, it really hasn't. I mean, there's been some discussion about the risks of using these lentiviruses, and we'll talk in a second about how we could do better now.

57:52

Yeah, People are going to hear putting viruses into cells and putting them into humans, and a bunch of people will freak out. But I promise you that things like adeno, which is like a cold virus, or lenti, which is similar to hiv, and of course, they didn't give her hiv. They changed the virus so they're not delivering hiv These viruses are incredible because they can create long lasting expression of genes that you deliberately put into them.

58:02

They're a shuttle.

58:26

It's an amazing application of biological understanding, right, that all of a sudden we been studying viruses because of the risk that they have, but we've learned that they can deliver that viruses have evolved to be very good shuttles and to deliver their genetic material into cells.

58:27

The way I think of it is the viruses have evolved to take advantage of our biology and our genes. And so we did the ultimate touche in these instances. Like, you're so good at hijacking our cells, DNA and proliferating. All right, we'll leverage you to help us as opposed to hurt us, right?

58:42

That's exactly right. And so that was done in 2012. Emily Whitehead was 8. It was 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.

59:02

So awesome.

59:23

And so no one could ignore that. This was just all of a sudden, this dogma that I had just been taught a couple of years early in medical school that we should ignore the cancer immunotherapy. We were just wrong. And all of a sudden, the field woke up and said, okay, the immune system is not just limited to treating viruses and bacteria, protecting us from viruses and bacteria. The immune system can be exploited and potentially re engineered to protect us from. From cancer and maybe other diseases. So that was 2012. 2012 also was the year that a paper got published in Science by Emmanuel Charpentier and Jennifer Doudna that introduced this new technology called crispr. And we'll talk about this. But CRISPR fundamentally is a tool to rewrite DNA sequences that came out in 2012. And on a personal level, 2012 was also the year that I moved to San Francisco to start a lab studying 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 an empty lab space at exactly the same moment 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 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 to 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 into immunotherapies that cure patients with different diseases, and then to go all the way and then actually use crispr to make t cells that can be input into patients with new levels of precision and power. And that's. That's in clinical trials now. We're now in clinical trials with these crispr engineered car T cells. And we're not just going after leukemias where these car T cells have historically worked, but we're also thinking about, can we make these work for the really common causes of cancer deaths, Solid tumors? And that's been a challenge, and we can talk about that. But getting t cells to find the right targets in tumors and then work inside of tumor environments, which are inherently immunosuppressant 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 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 resist all the tricks that cancers throw at it to be more. And I think we're on the brink of having precise crispr engineered cells that will, I hope, start to melt away cancers without the side effects of chemotherapy.

59:24

Amazing. Just amazing. And the story of this young woman is spectacular. I have two questions before we talk about crispr technology. The first one is, is it true? I believe it is. But is it true that cancer risk goes up as we get older? And if so, why? So that's the first question. And then the other question has to do with how the immunotherapy that you described Was able to target the cancer and not cause problems elsewhere, which is kind of the major issue of chemo and radiation therapy. But the first question, again, was, why more mutations as we get older?

1:02:41

So I think there's a few cancers that peak in childhood, and there's risk as the body's developing a certain cancer, Childhood cancers, and there's childhood leukemias, for example, and that like when we talk about emily whitehead. But most cancers, as you said. Exactly as you said that there's this sort of increase, and they're largely disease of later stages of life, I think that the reason for that is. Remember when we talked about what causes cancer? It's this evolution where certain cells start to accumulate mutations. Numerically, a lot of those cells that have the mutations will die off. And it's just a game that unfolds over time. And the more time you have cells dividing and sticking around in the body, they're accumulating more damage. And eventually you're more likely that that damage would actually transform the cells into a cancer cell. So time is a big factor here. Time and just accumulated damage.

1:03:25

And the other question was, how is it that the lentivirus knows to the lentiviral cargo carrying T cells know to attack the cancer and not something else.

1:04:16

So this is a key question for the field. Right. And I think one of the things that worked incredibly well was a brilliant choice by a group of scientists in different, a few different places that converged on the target that was used in the first car T cell. And what the target is known is a protein called CD19. That's just the name of this thing that's found on a lot of different types of B cells. So this brings us back to this discussion. The leukemias themselves are a cancer of the immune cells. So they're cancer of B cells. And CD19 is found on the surface of many a large number of different types of B cell leukemias and lymphomas.

1:04:31

I see.

1:05:15

I think one of the things that turns out to be serendipitous here is that B cells themselves, natural healthy B cells, actually also have CD19 on their surface. What just turns out to be serendipitous is that the body can tolerate those cells going away. And so what has made this a particularly effective and safe and relatively well tolerated treatment for cancer is that the collateral damage is actually not that damaging. That T cells in this case, are not strictly distinguishing between cancer and health. They're not just getting the leukemia cells, they are getting collateral B cells. But by and large, to a first approximation, people can live without those cells. And so that side effect has just been tolerable. Finding that balance gets harder and harder for more cancers. If you start to think about pancreatic cancer or brain cancer, finding targets that if you hit the healthy pancreas or the healthy brain, are not toxic, it's harder and harder. So people are thinking about more and more sophisticated ways to look for these targets that are selectively found on the cancer cell and not on the healthy cell, or to think about ways that you might actually make the cell depend on recognizing multiple Features so that you can have what's sometimes talked about as like a two factor authentication. Like, like the T cell will only kill cancer if it finds this and this and that combination of things are not found on healthy cells, even if one or the other might be. So people are thinking about how do we get more sophisticated about building these discrimination systems into T cells. The building blocks are there, but the specifics for each cancer have to be invented. But we have the tools to do that.

1:05:16

Awesome. Before we talk about crispr, there was one other question that I know many people will be thinking about. A few years back, maybe five, 10 years back, there was a lot of discussion, maybe even some enthusiasm about ketogenic diets to treat or prevent cancer. And my understanding from looking at that literature was that for some cancers, it perhaps I want to bold, underline and capitalize. Perhaps might help. But for other cancers, it could make things worse. And then I also more recently started hearing about low glutamine diets. And of course, this is the way the Internet works. But I did see some papers in some decent journals that at least were exploring this. So are low. They're just low carb. Let's call it what they are. Ketogenic diets. Have they been shown to be useful for treatment or avoidance of cancer?

1:07:02

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

1:08:00

Okay. My guess is that people are still looking at this, but there was also the idea that they could be useful for certain forms of dementia. There was an effort to call dementia type 3 diabetes. But my understanding from talking to the experts in this is that it might help through indirect mechanisms, but that it's not going to solve the problem. Okay, well, thanks for entertaining that little cul de sac that I created, crispr. Tell us the story of crispr, 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. It's here, it's powerful, it scares certain people, it excites other people. 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 how science works. And that's important too.

1:08:03

I think it's exactly true. I think it is a perfect illustration of something where a discovery happened that no one was planning, but changed biology. Let me tell you this story in two separate arcs. One arc is the arc of understanding DNA, if you go back to Watson and Crick, it's understanding the double helix to understand the structure of what a DNA sequence is that matures. We learn how to sequence, to understand, to be able to measure a row of A T's and C's and G's that in whatever combination they are, will start to be the building blocks for programming which proteins get made inside a single cell. And then around 2000, we get to the first draft of the human genome, which is this multibillion dollar project across the world to come up with a draft of one human genome sequence milestone for biology and medicine. And then DNA sequencing technologies continue to improve and cost comes down. We're getting to the point where we can start to measure big chunks of our DNA at increasingly affordable costs. And people were starting to understand the differences between people with DNA at the level of at least statistics. Okay, people with this disease are more likely to have this gene than that. But we're getting to some limit of what we can do just by sequencing DNA. All of a sudden, 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 maturing, we're desperately looking for a tool to say, well, now we want to, as we have all the sequences, we want to be able to see what happens if you change a sequence. And people were stumbling around looking for different tools. There was a range of these things. There were zinc fingers. Lentivirus was another one that we just talked about that with different degrees of efficiency. And people were trying 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 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 and bacteria, started studying these repeat sequences and what they were doing. And little by little by little, it was worked out that these repeat sequences actually formed the basis of a kind of immune system for bacteria. Now we talked about the human immune system. Bacteria are just an individual cell, but they're also susceptible to infections, which is sort of a strange idea. Bacteria cause infections in us, but there's this arms race between organisms.

1:09:05

Everyone's trying to kill everyone else.

1:12:05

And so bacteria are constantly being bombarded by certain types of viruses. They're called bacteriophage viruses and they've evolved a series of bacteria have evolved a series of defense mechanisms to protect themselves from these viruses. CRISPR turns out to be a bacterial defense mechanism against viruses, which is kind of amazing that this thing that has entered into popular culture is 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 CRISPR works to protect against itself, the protection bacteria from viruses, is that it can recognize particular sequences of DNA, which are virus sequences, and discriminate whether it's a virus sequence or its own bacteria sequence. And it actually does that by scanning across the DNA and finding something that's recognized as a virus target and not a bacteria target. And when it finds it, it makes a cut. Okay, now this sounds technical, obscure, but what was recognized and this became the basis for a Nobel prize with Jennifer Doudna and Emmanuel Charpentier. Many people around the world have contributed to this field. What was realized was that this could be repurposed as 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 just 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 the 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. 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 sequence. It's the way that it cuts that has made it really catch on in a way that none of these earlier technologies do. So crispr, if you think of it as a, it's 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, 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. And what's so special about that is that we actually know with 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 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.

1:12:07

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 the related question is, if you're going to introduce a gene sequence there, how do you ensure that there aren't downstream effects?

1:17:07

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. How do you get more and more precise? And it's come a long way, but nothing's perfect. 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 6. Do you actually evidently accidentally ever cut anywhere else? And there's a range. Sometimes some sequences are a little bit more promiscuous than others. But we've gotten quite good at getting more and more precise to say, okay, we're making these high fidelity cuts 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 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. And 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. 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 a deaminase 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. That DNA doesn't just get enacted by DNA sequences, but can actually pieces of it can be active or inactive. And this is called epigenetics, where there can be a stable program of things getting turned on or off without any change in the A's and T's and C's and G's. And now we and others are using CRISPR based epigenetic editing. 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 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 way.

1:17:37

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1:22:03

I'm curious about getting CRISPR into the cells of interest. You know the lentivirus example that you gave before? My understanding is it involved harvesting some T cells, introducing the lentivirus with the cargo that you want, putting that back into circulation, and the T cells know where to go and know what to do. For a lot of cell types like neurons in the brain, liver cells, pancreatic cells, I could imagine a surgery where you inject directly into those organs. But wouldn't it be wonderful if you could get the cells of interest without having to be so invasive? So what's being done there in Terms of trafficking CRISPR2 Appropriate cell types and or organs, and then that sort of seeds. Another question that I'll hold off on about whether we should be banking cells for what's coming.

1:22:18

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

1:23:20

I do, too. I mean, you're taking us to 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 we are peering over into what's next, like what your children and my children and probably our parents also will be able to benefit from in the next 10 years, maybe sooner.

1:23:24

Yeah, we're really talking about things that are happening now and happening at an accelerating rate. So you asked. Part of what just 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? So I told you, let me go backwards and then I'll go forward. I told you that in 2012, 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 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. 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 sort of tripled down on this is what my lab was going to do if we were going to 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 another serendipitous run in. 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 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 CRISPR protein. So we had protein and RNA that we could make in a test tube. 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, 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.

1:23:48

Electroporation.

1:25:54

Electroporation.

1:25:55

Oh, man. During my graduate career, I electroporated a lot of. Well, I can just say it now, because I don't do it anymore. Electroporated. A lot of brains of intact animals, you inject DNA, it's floating around in the local tissue. You pass some square wave current, and the assumption is that it creates little transient pores in the cell membrane and it gets in. And sometimes you end up with four cells transfected. And sometimes you end up with 40,000 cells transfected. It's a wildly useful technique, but it's a little bit hit or miss.

1:25:56

That's perfect description. And so my first postdoc in my lab, Kathryn Schumann, sat there and tested different electroporation conditions all during these little

1:26:33

pulse pulse, 12 pulses, long pulses.

1:26:43

You're taking me back to my graduate and to some extent my postdoctoral years. It's unclear for given tissues, for given sequences, what's going to go into cells, what's going to happen, not kill the cells.

1:26:46

We were walking this tightrope of how do you make this pores big enough that CRISPR will get in, but that the cells don't die. And we did it, and we did it, and we've optimized this. And it was one of those things when it happens, you see it and you just realize it's binary. All of a sudden you're editing DNA inside of T cells. And 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 are gene edited.

1:26:57

She figured out the protocol, she really

1:27:35

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 technology worked, a company called Arsenal biosciences that's now in clinical trials. It's actually in its 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, 10,000 nucleotides of DNA code that put in a sequence of a combination of different receptors, including a car and additional gene enhancements that will make these T cells more powerful in a tumor microenvironment.

1:27:36

And then they go into the bloodstream, they navigate to the prostate, and they start fighting the cancer cells. And I imagine you can also put. It sounds like you're putting some kind of resilience genes in there as well.

1:29:01

That's exactly.

1:29:12

To bolster the healthy cells, to bolster

1:29:13

the T cells that carry these receptors, to make them persist longer. Exactly.

1:29:15

Awesome.

1:29:21

That's happening. And the way that that happens is that a patient will be selected, will go in for a blood donation, give a rather large blood donation, but those cells are then shipped to a facility that arsenal maintains. The electroporation happens in the centralized facilities. The cells get grown up for a couple of days and tested. They get frozen down and then sent back to the patient, where the cells are then thawed, and they get. It's the equivalent of a blood transfusion. Now, their own cells have been supercharged to allow them to recognize cancer, but also to have, as you said, added resilience, added strength in that battle against cancer.

1:29:21

The cells that have been modified by the CRISPR Cas9, they're sitting in this bag that get infused. Are they designed. Is the CRISPR designed to only go after the prostate cancer cells? Or is there some version of this where you can inoculate against a number of different cancers? In other words, if I'm understanding correctly, if they're sort of canonical mutation sequences that occur in all cancerous cells, Is there a version of this where I give some blood, you or a company? Probably a company electroporates them with the CRISPR Cas 9 system, brings in resilience genes for the T cells for my T cells, plus some attack genes. Right. So that are going to destroy the cancer cells. And then I get an infusion of these when I turn. I'm 50 now, so like 52. And then it protects against all cancers that probably are forming at multiple sites throughout my body. Little mutations here, low mutations there. Hopefully they don't, you know, proliferate. But is there a way to just short circuit cancer body wide?

1:30:01

I think that's a hope that all of us have to some extent. I think these technologies get proven out in patients where the risk benefit of an unproven technology is tolerated. And I think that in reality that means that patients who have exhausted other treatment opportunities get treated. And often those are the sickest patients. And I think there's good reasons for ethics where that's where we start. But our hope is that these technologies eventually will be proven to be safe. They'll get more and more precise. I hope the cost would go down. And I don't know, you talk about the other extreme of doing it preventatively, but at least we should start marching earlier and earlier in the course of diagnosis. And the hope is that we're already seeing improved tools for early diagnosis of cancer where we're detecting the earlier signs of cancer. It'd be nice if we have the ability to start treating those early cancers that might be the ones that are the most responsive to the immune system. And then beyond that, preventative would be even better. I think to get there, if we really want to scale up, I think we also have to think about you sort of going back to your last question about delivery. Maybe it's not always going to be these cells getting shipped to a centralized factory and electroporated. Although that's been incredibly powerful and it's not stopping now. We're actually starting academically in an institute that I run, the Gladstone UCSF Institute of Genomic immunology. We're starting a philanthropically funded CRISPR trial for multiple myeloma where we're using a different genetic program. So there's a huge number of diseases where we are thinking about what can we do with existing technologies. We're also starting to look for ways that the deliveries of the future will happen. And different people are coming up with different solutions. But One emerging trend is that rather than taking the cells out of the body and then exposing them to CRISPR in these targeted ways, with electroporation, what if we could put CRISPR into the body and just send it and address it just to the cells that we want to modify. We're interested in the T cells. Someone else might be interested in modifying lungs or heart or neurons. Right. For different diseases. And that is a field that is now exploding thinking about technologies. It's another area where there's just tools that are happening so fast.

1:31:18

You know, when I was a postdoc, it was all about, it seemed for a few years like different ways to get genes into cells. So there's electroporation, there are lentiviruses, there are adenoviruses, there are calcium phosphate transfection. There was an on and on. One of the things that was kind of interesting, but at the time didn't really go anywhere, was customized little liposomes, like little fatty bubbles. Cause fatty stuff can get onto and through cell membranes. So it makes good sense, but with some sort of zip coding so that you could inject these fatty bubbles 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?

1:33:47

Dramatically?

1:34:33

Oh, great.

1:34:34

Dramatic. Relieved to hear.

1:34:35

And relieved to hear. I wasn't the one that had to do the work because I knew a lot of very frustrated people working on liposomes. Fortunately for me, electroporation and adenoviruses worked spectacularly well for my experiments. But a lot of people needed cell type specific transfection through a vein injection.

1:34:36

So all of these things have gone under rapid progress. Let's talk about the viruses. We talked about viruses as a tool, as a shuttle of DNA. They naturally, each one will have some range of what cells it would infect for a virus. This is called tropism. What cells are susceptible to infection with any virus? Those would be the cells that you'd be able to deliver genetic material to with an engineered virus. People have really advanced engineered tropism, engineering what cells a virus will deliver material to. And that can be dialed in quite precisely now in a number of different ways. So people are working on engineered viruses that 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 that are essentially Viruses that can just deliver either DNA or proteins to a cell that's specified by what that virus tropism is. And people are working on engineering these tropisms with a lot of technologies, because

1:34:56

you could put drugs in them, too. I mean, we talk about SSRIs, have all these side effects. Well, that's because you're getting serotonin increases at locations you don't want it. You could imagine only getting drugs to certain cells. To me, it's super exciting and just seems so fundamental. So I'm relieved to hear that there's progress being made.

1:36:01

Anything that can be genetically encoded, you can start imagining these types of targeting. Now, you asked about liposomes. Now liposomes have kind of come up with. Our new name is lipid nanoparticles.

1:36:23

Lipid nanoparticles. It kind of rolls off the tongue nicely.

1:36:35

And the abbreviation we use is lnps. But a billion people around the world have now been injected with LNPs. LNPs are the technology that delivered MRNA vaccines.

1:36:37

Ah, okay. That'll raise some eyebrows. No, we're going to talk about vaccines. Listen, we're going into it all today. They were liposome bound, essentially.

1:36:49

These are lipids that can deliver genetic material to cells. And this was done locally for the COVID vaccine. But people are now engineering them with the targeting molecules that you described so that they go to particular cells. If you inject them into the body, lipid nanoparticles, those naturally tend to go to the liver. So people are using these already to cure genetic diseases where the genetic burden is affecting the cells in the liver. Because you can deliver CRISPR to cells in the liver pretty robustly with these. I have my strong view on the COVID vaccine. I think it was a miracle that we were able to develop something on a short timeline to address a pandemic that was killing people. But I understand there's controversy. Leaving that aside, lipid nanoparticles are. It's amazing that we were able to do this, that we took something that was an idea. Most people thought it would be an obscure technical thing like you talked about. Would it ever work? All of a sudden it could be manufactured at scale, could deliver a synthetic piece of MRNA to give a temporary instruction to cell cells to make a protein to protect us. And whether that's for Covid or for other things, all of a sudden we're again, just keep coming back to this theme where there's more and more ways that we can not only understand biology, but that we can intervene in it to treat disease. And so now we're talking about something totally different. We're talking about delivering crispr, which is not an MRNA vaccine, but we're talking about how would we get CRISPR into cells, or how would we get extra pieces of genetic material, which might be an mRNA, into a T cell. All of this can now be done even beyond the vaccine world with the same kind of building blocks of technologies like lipid nanoparticles. Actually, there's a company out of the University of Pennsylvania that actually developed recently a technology to make lipid nanoparticles that could be injected into the bloodstream. Think of them as these little fat bubbles, exactly as you said. But in them, they included a protein that would recognize something on the surface of T cells, so that as these lipid bubbles were going through the blood, they would stick preferentially to T cells and deliver MRNA to T cells. And you could actually put in an MRNA into T cells that would temporarily make a gene that would encode a car, these artificial receptors against cancer. And they've done this now in testing in a number of models. They can actually make these car T cells by injecting lipid nanoparticles into the body without ever taking the T cells out of the bloodstream. And I think we're going to see more and more things like that. The pharma industry is all of a sudden saying there's more ways that we can make drugs. Things don't have to just be pills anymore. They can be engineered proteins or lipid nanoparticles or viruses or engineered cells, whatever is going to be most important, effective at getting to the root cause of disease.

1:37:00

I want to just talk about the COVID vaccine briefly, because in my role as a public health educator, I was exposed to a lot of voices, and I can't speak for everybody, certainly, but I think that at least three of the things that caused a lot of dividends around the MRNA vaccines were, first of all, the difference between mandates versus optionality. We don't have to go there, but I think that was a major player. Right. People, especially Americans, don't like to be told what to do.

1:39:58

I've noticed that.

1:40:42

Okay. Second of all, it was closely related to notions of the shutdown which differentially impacted people. And that's an understatement. Right. Some people maintained paychecks, some people didn't. Some people could work, some people couldn't. So there was that. I'm not trying to soften anything here, but I think that the vaccines were nested in A bunch of other issues. 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 can imagine a situation where I would want to put an MRNA into me 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?

1:40:42

I'll answer the specific question, but I think the context that you give is also a really important part of this. And I would take one second to talk about this. I think to answer your first question, we talked about DNA as 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 for a particular protein. The idea of an MRNA vaccine is that you're using this temporary template so that 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. You can always imagine the extreme outliers of ways that this could last longer or not. But fundamentally, this is. You're putting in an MRNA that gives a temporary instruction to the cell to make a small part of the COVID vaccine. Now we have the COVID virus very small part right now, just by comparison, if you get infected with COVID you're also going to get Covid. MRNA is transcribed in your cells. So 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, of that Covid genome that we're using as a vaccine. So I think it's important to think about the risks in the context of the virus versus what we're doing with a vaccine. So I got the COVID vaccine enthusiastically and actually, I think overwhelmingly. I mean, I know overwhelmingly my immunology colleagues did the same in people who live in this world of immunology. A great enthusiasm that this could be done and built. Now, that doesn't answer what you said about the cultural phenomenon. I'm talking just as a person, not as an immunologist, but. But I think we probably haven't done enough to talk about the trauma that we went through as a nation during COVID of being fractured by people dying on one hand, and all the negative consequences, as you said, of shutdown, shutdown of economic life, shutdown of social life. 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. I'll just give one anecdote. While 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 speed race that was actually, I think, one of the highlights of the first Trump administration operation warp speed, to streamline and get coordination both on the science and the regulatory side to get vaccines approved in an extraordinary timeline, taking advantage of a number of technologies and making them all. So I was watching this science unfold with some optimism, but also watching the trust in science being eroded. I developed a side hobby, which is I've gone back. I've been reading presidential biographies sequentially. This is just a side hobby now. And thinking about this sort of frustration 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 Philadelphia. And actually the early parties that were forming, the Federalists and the Democrats, actually took wildly dissenting views of how to deal with an epidemic. They had different views of what caused it, whether it was outside contagion or sanitation. And the Democrats, at that time, the Jeffersonian Democrats, were in favor of really extreme bloodletting techniques. And the Hamiltonians, the Federalists, had a totally different set of techniques of baths and more gentle treatments, and they just couldn't see to eye to eye. Why am I saying all this? I think it's not new territory 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 to them from different perspectives. And 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 a pandemic or an epidemic.

1:41:47

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 and unfortunately Walter Isaacson hasn't written them all. I love his books. So how do you select the author of each biography?

1:47:07

This is an honor. This is a project that I spend a lot of time each one I go through a period of indecision about which one I should read. I can share my list. I'm not done yet. This has been over several years. I've been I'm now up to World War II.

1:47:23

You should do a podcast someday. Just know in your copious amounts of spare time, not as a husband, father, running a giant lab, et cetera, and physician. You could do a podcast and teach us what you learned. Anyway, awesome.

1:47:38

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 100 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 100 biomarkers key to your physical and mental health, but it also analyzes these results and provides insight 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.

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I'd been eating a lot of tuna

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1:48:56

related to technologies to killing or altering cells that we didn't cover. But since we've touched on a number of them, the lipid nanoparticles, lentiviruses, since

1:49:40

we're

1:49:53

in a previous lifetime, I used 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 case we use Saporin toxin, which I think is most infamous because it was put on the tip of an umbrella and used to assassinate somebody on a bridge someplace in some sort of international spy warfare in the last 20 years or so. Saporine 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. Has that been tried in cancer, directing toxins towards cancer cells?

1:49:55

The short answer is yes. It's a really interesting area. And what that toxin is can almost be thought of as like modular that you can put a different. That you can think of it as two components. You have a targeting component. An antibody is a natural one where an antibody is evolved to recognize one particular type of protein that can be the thing that targets something on the surface of cancer cells. People have then developed what's called antibody drug conjugates or basically a drug or something that's going to kill the cell gets appended to that antibody. And so 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 that will be recognized by that antibody. It doesn't have to be drugs. People are thinking about other things. People are now trying to attach radioactive isotopes. There's radioligand therapies that can be attached to these things. And I think in an extreme that's essentially what we're doing with these T cell therapies too. We're also using, when I've talked about this car, the chimeric antigen receptor. The outside of it, that is the sensor that's being used is also a part of an antibody. And so essentially what we're doing is now using the antibody to target. But instead of dragging along a drug it's dragging along a cell. And so when that's engaged, the T cell is there and the T cell becomes the killing module. But the T cell not only kills the cancer cell, but could potentially be used to amplify that response, could release things and recruit other things. So I think this general way of thinking about designing things to bring 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 I think this is a proprietary term, but it can be called a bispecific or a bite. The bite is a proprietary term, but basically these are two headed antibodies. One side will recognize a cancer cell and the other side will recognize a T cell and essentially bring these things together so that you get the T cell action locally to the cancer cell without having to do any genetic modification to the T cell. You actually just take advantage of T cells that are already in the body. So all of these things are now under very active developments and some of them are approved, others are still in development.

1:50:52

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

1:53:46

I'll push it one step further. I'm actually helping to organize a cancer immunotherapy conference here in la. I'm simultaneously here 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 an advisor to Amgen. But this talk was, and Amgen has been one of the leaders in these bites. I think they actually trademarked this idea of bispecific. T cell engager. These are antibody fragments. But 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 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 for these modular multifaceted cell engagers or drug engagers or any of these other things. So this is another area where the crosstalk between experimental capabilities and computational capabilities is further accelerating what's possible.

1:54:13

Incredible. Would you mind if I asked a couple of questions about the kind of science, sociology and ethics around crispr?

1:55:45

No, I would love it.

1:55:55

I'll keep this brief. A few years back, we all learned, meaning the entire world learned, that a scientist in China had done a CRISPR CAS experiment on babies. I don't know when he did the modification. My guess is it was in utero. 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 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. 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.

1:55:56

It was like there was this kind

1:56:52

of moment where no one really knew what to do. 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 what he had learned at Stanford, what was done at Stanford. And the stance, as I recall, was everyone just kind of 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 kind of the last we ever heard about him were those kids. The Chinese government condemned it publicly. I think they said he was going to be punished, but it wasn't clear if he was going to be punished by being put in a jail cell, being fined, or given a larger laboratory and more resources. It was very unclear. It's playing God at some level, 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 awareness, if any, that CRISPR in otherwise healthy humans has continued and where you think this is all going.

1:56:53

Yeah, I think you capture a lot of that moment. I wasn't there, but there was an international CRISPR conference that was being held, I believe in Hong Kong at the time. And the scientist got a. And announced with extraordinary pride 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 had happened was that there were two twins who were. There 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 if it's deleted, can confer resistance to HIV. This is a gene called CCR5. There's people who naturally have a certain mutation in this at some frequency, and mutations in this gene confer resistance to HIV if they're naturally occurring. So that was the supposed rationale.

1:58:22

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

1:59:29

It was a prophylaxis against 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 through sperm washing and things that can be done that would, from my understanding, essentially reduce the risk to near zero of transmission from a father to an embryo. So I think it was a bit of a manufactured need, but there was this supposed justification. Second of all, it was done. 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 publicity that was released. So I'm sort of piecing this together from what was public at that time, but I don't think any journal ever published this in any peer reviewed context. They did this in concert with essentially IVF techniques. So they were fertilizing embryos with this father's sperm as 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, 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, how much was informed about what the actual benefits would be to these patients. My understanding is that he got up and Ida wasn't in the room. But I do think that there was some degree of immediate horror that this was being announced and that it was unfolding in this way and that it hadn't been considered, it was not ready. In the wake of that, the Chinese government then announced that they were going to punish this. And I don't know the details, but I believe that he underwent some period of house arrest.

1:59:34

Okay. He was punished.

2:01:44

I believe so. I think after there was some degree of scientific outrage at this point.

2:01:46

Yeah, there was this pause moment that lasted maybe a week or two. Okay, well, you're clarifying a lot of

2:01:53

the important details, but my understanding, again, is that he's now free and I think is restarting a lab. I don't think in China. I think somewhere else. So the story might not be over yet. So that's my understanding of the facts. I'll tell you now what I think.

2:02:00

Yeah, please.

2:02:20

I actually have a pretty hard line position on this, which I'm not sure all my colleagues would agree with. But I think that we should have a line in the sand where we do not introduce genetic edits that will be passed on to the next generation. I told you, I've dedicated my life now to creating CRISPR technologies to engineer individual cells in the immune system. But these are what we call somatic. These are making edits to the DNA in individual cells where those genetic consequences will be passed on to the daughter cells, but not to the next generation of human. Because we're not making genetic edits in sperm or in eggs. If you do it in an embryo, all of a sudden, every cell in the developing embryo will have it, including sperm and egg. And now you've not only made a genetic change to treat a disease or in this case, to prevent a disease, as you said, in some cases, it'll be imagined to make an enhancement. People have talked about, maybe you want to add, we know, genes that would make people be more muscular, or will there be a rush to or enhanced memory?

2:02:21

I mean, many years ago, there was a paper. I mean, it had some issues with replication down the line, but where I think it was Joe Chen at Princeton introduced maybe a mutant or an extra. I forget now, it's been a while. Case in point, I clearly don't have this receptor to the NMDA receptor which is involved in plasticity in a sub region of the hippocampus. The idea was they were trying to make super smart mice.

2:03:27

I remember that. That made quite a splash at the time.

2:03:53

I forget where that went. Maybe Joe followed up on that, I don't know. But that would be the sort of thing that people are both excited about and concerned about. Could you confer your offspring with better memory genes? But of course we have no idea if that's a good or a bad thing. Forgetting certain things is very useful as well.

2:03:56

I completely agree with you and I think the point you made is a key one, that we do have a. We do live in a world where people do IVF and we do pre implantation genetic testing and we select people have the option to select non implant embryos that have certain mutations. That's already a level of avoiding disease in the next generation. If there's a severe mutation, I think it's a qualitatively different step to then not just select, but to actually make a genetic change. All of a sudden now you're really hampering. You have the ability to make some kind of mass produced genetic edit in many embryos. I worry a lot about what this means for our offspring if they are designed rather than just born by chance. I worry about fads. When you think about the Pinterest culture that we live in, where people see something on Pinterest and want to follow on. I worry deeply about losing human diversity if we see fads in what genes are popular for our offspring. And people can order those in concert with ivf. And I don't think we gain enough to come close to what we would lose as a society if we embark on that journey of editing offspring.

2:04:17

Appreciate the clear stance and answer. As long as we're there, I'd love your thoughts on some of the newer technologies that are only available to those that can afford them. So that's an important caveat for deep sequencing embryos from ivf. So typically with ivf, check to see that they're chromosomally normal, that they're euploid, as they say, and they'll do some sequencing of the parents, maybe of the embryos as well for certain mutations. But there's this whole other industry now. I believe a company in the Bay Area, Orchid, is probably the most popular one or well known one where if you pay a certain amount of money, they'll deep sequence. If you pay more, they'll deeper sequence. And so you're getting some additional readout of potential disease genes. And I've looked at that technology and they're very clear that at some point they can't draw a causal relationship between say like a neuro ligand mutation and autism. But there are these implications based on the animal data. And so it starts to become this, this. It's not gene editing, but it is deeper and deeper. Gene sequencing based selection of embryos.

2:05:43

Yeah, first of all, I'm sympathetic to the idea. Right. Like we want to protect our kids from suffering and from disease. Right. And I understand the idea of doing pre implantation genetic testing if you want to avoid a mutation or chromosomal abnormalities that would really impair lifespan or quality of life for your offspring. The impulse we know that this sort of straightforward chromosomal testing that's done from the first level 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 cause severe disease. But there's a lot that become probabilistic and statistical and I think we're over promising what can be delivered. 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 it's not an axis that actually exists. There aren't categorically more desirable or less desirable that we want diverse people. And how successful you're going to be as an interplay of how your genes come around and influence your community, your environment. Those are unknowable from just looking at a DNA sequence alone. So I think that it introduces a false axis. There's another book that I would recommend here that I read years ago and actually I'm probably overdue to go back and reread this. This predates CRISPR technology, but 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 access of perfection rather than embracing the beauty of chance and happenstance, which is a part of our relationship with our kids, with ourselves, of thinking, okay, this is the human experience of your product of some degree of chance and circumstance.

2:06:57

I'll definitely check out the book. I know the whole point of life is not to be A high performer. But I'll just say as an example, I know of no single very successful person that doesn't have some thing about themselves that initially they disliked or felt that they had to overcome, which led them to pursue certain things, hopefully in a healthy way, and that they eventually came to embrace and are now grateful for. I know of no exception to that. It's just kind of. It's the story of humans, in many ways. It's a story of humans, in fact, people who perhaps are told that they're perfect in every dimension their entire lives. 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 fragility that that can introduce to the psyche.

2:09:17

I think that's really well said. I think it goes in both ways. I think things that we think. I think our hardships or disabilities often end up being the things that make us who we are and make us more sympathetic, give us added depth as humans. And the things that we think are the things that make us perfect are the things that are really holding us back or creating all sorts of false ideas that limit us.

2:10:17

I couldn't agree more. I'd love to know what right now you're most excited about for your own intellectual enrichment and in your lab. And what you really feel is the thing that has the most electricity for you. 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 that. That we can look forward to.

2:10:43

Thanks for asking that. So I'm going to give a little bit of a long, meandering answer that.

2:11:13

I mean, listen, when it comes to

2:11:19

me, you don't have to.

2:11:20

Succinct is not something that exists in my neural circuitry, although I try.

2:11:21

So I see this moment. I talked about clinical trials that are already filling me with hope. I talked about a biotech trial that I'm associated with for prostate cancer. I talked about an academic trial that I 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 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.

2:11:26

Fantastic. Could you just mention a few other disease targets? I know a few people with fibromyalgia. They suffer tremendously.

2:12:19

Fibromyalgia is a disease that we just don't understand. That is talk about understudied diseases. I think fibromyalgia is something that gets bucketed in a certain way, and we just have not figured out what it really is, what causes it. And so 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 talking about various engineer T cell trials for rheumatoid arthritis, for childhood diabetes, for multiple sclerosis, and on and on. But those are a number that people are thinking about different types of immunotherapies, including gene and edited T cells to treat these autoimmune diseases. So I'm already, I guess what I'm saying is excited about the near future of things that have come out of decades of lab work from 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 have one of the great jobs out there is there's about 30 people in my lab. I get the joy of ideas bubbling up. The ideas at 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. And I can't believe the surprises that are coming. So I want to give you a couple of these. So just looking backwards to 2013, 2014, we were struggling to see if we could get CRISPR 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 and giving them characteristics that are going to be strong against cancer. So we are able to do 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 race them against each other for one characteristic, which ones would start to make one cytokine. I 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. This is a technology called single cell RNA sequencing. So we measure now simultaneously all of the RNA that's in that cell, 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 at a massive of scale Directly in primary human immune cells. We just released 22 million cells where each one has a different CRISPR gene inactivated. And we get a map of this. 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 in different conditions. As a sequel to the genome project, 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 as a basis for massive computational analysis. It's providing us a real roadmap of how cells are wired. That will be the instruction manual for the next generation of T cell immunotherapies. That the lessons that we learn about how every gene behaves Are now going to be actionable. And these are going to be genes that we tune or epigenetically edit or inactivate or add to genes that we will now have a recipe book for. What do we want an immune cell to do? What do we want it to recognize? Where do we want it to go? And we'll have a cheat sheet that tells us, okay, 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 want to go after.

2:12:26

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

2:17:55

Well, I think the good news is that I never know what the answer is. I was going to say the good news is that we largely have T cells now. Are there exceptions to that? Yes, there are patients who are getting treated for certain types of cancer and the chemotherapy that they're getting depletes their T cells. It's hard to know. I guess 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 I hope reactivate them, re endow them with powers. I would be disappointed if in the future we would need to go back and take banked T cells and not be able to re engineer cells that are already there. Are there edge cases where it might be? But it's not something that I would tell people to go out and do. It's not something I'm doing.

2:18:00

Yeah, I would only do it if you told me to. A colleague of yours, Yamanaka, won a Nobel prize for essentially showing that you can take a skin cell, put it in a dish, give it Yamanaka factors, as it were, four, in some cases, only three transcription factors, and essentially revert that cell to a stem cell 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, reverting them to the stem cell state? In my mind, I always thought, well, if I ever need more cells of a given, I can always, assuming I'm alive, 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 Huberman, in my case, Marcin, in your case, obviously cells that if, God forbid, I needed a bunch of pancreatic islet cells, boom, they could have those within a week.

2:18:55

This field is something that's been amazing to watch there's been ups and downs of it, of this induced pluripotent stem cell field that Shinya Yamanaka opened up. 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.

2:20:00

That's what I was thinking. You don't even want to draw blood.

2:20:20

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 would be cost effective for everyone to have their IPSLS ready to go. I understand in conversation with Shenya Yamanaka that one of the things that he's been involved with is actually building sort of a bank of IPS cells that would be compatible, immune compatible with. With broad sets of different people, so that it could essentially be used as a transplant bank, which might be a way to be like an intermediate step that there would be IPS cells available that could be transplanted with various degrees of ease into different people. And then I do think that I hope it gets easier and easier to make IPS cells that are matched to any patient when they're needed. But I mean, again, these different threads of things that being able to make endless supplies of any cell, direct them to any tissue type, and then being able to program them when the language of CRISPR actually it's worth some moment. In 2020, I moved my lab from the main branch of UCSF to a separate research institute in San Francisco called the Gladstone Institutes. It's a non profit research institute. My grad students still come from ucsf, University of California, San Francisco, but my lab's at Gladstone. And one of the reasons that I moved my lab to Gladstone was a conversation. When they were recruiting me, they brought me into the President's office. And in the president of Gladstone's office was Shinya Yamanaka, who maintains a lab at Gladstone, and Jennifer Doudna, who also maintains a lab at Gladstone.

2:20:23

You had to say, yes, they're very clever. You had some psychologists, they got your number, so to speak.

2:22:08

I described this and I think this not just a cliche. I actually remember kind of like that feeling of hair sticking up on the back of your head of like, oh, all of a sudden these are the technologies that these two humans have made possible and others. But we can now program what the epigenetic state of a cell is thanks to the Yamanaka factors. You can dial between skin and embryo and then back to anything else. And then not only epigenetically program the cell, but take the power of CRISPR and genetically program. And when you put these things together, all of a sudden we have this ability to imagine programmable cells that we can dial in and direct their behavior to either regenerate or to, in the case of the immune system, survey the body and get to the root cause of disease. And my imagination still lies at that intersection of what's possible. When we combine that with immunology, I love it.

2:22:15

One question I don't expect you to answer, but your enthusiasm for this is tangible. I'm excited. I know people listening are. And the question is, how do you sleep at night? It's so exciting. The tools, they're here. And mostly I want to say thank you. Thank you for coming here today and giving us a absolute masterclass on the immune system, on cancer, on the technologies to improve the immune system, combat autoimmune diseases. I mean, we got into molecular biology with some considerable degree of depth and thanks to you, it was incredibly clear. I know people learned a ton. I know I learned a ton of. And I'm super excited about what you're doing. Also. Just the heart and soul, there are no other words really. I think those are apt. The heart and soul that you put into your work is so clear and you are definitely in the right job. So just one request is that you come back and talk to us again when the next advancements are made. We'd love to have you back.

2:23:13

I'd be honored and I just really want to thank you. There are not enough forums that are dedicated really to the depth to talk about science. So much of the joy of science is in the details and you do such a great job of letting those details really come through and sharing them broadly. So it's an honor to be here.

2:24:16

Well, thank you. It's a labor of love and I've loved this. So come back again.

2:24:36

Thanks.

2:24:41

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 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 30 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 pre sale@protographsbook.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.

2:24:42