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

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 and allowed does not exist in nature. When those T-cells get re-infused into a patient the way that you get a blood transfusion, those cars are directed to go against cancers. Welcome to the Youberman Lab podcast where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford's

School of Medicine. My guest today is Dr. Alex Morrison.

Dr. Alex Morrison is a medical doctor and scientist at the University of California, San Francisco.

He's developing new ways to reprogram the immune system to cure cancers. Today we discuss how your immune system works, how auto-munity works and how gene editing

“and other new technologies can be successfully leveraged to defeat childhood and adult cancers.”

Dr. Morrison is truly one of a kind in his understanding of the clinical aspects of cancer treatment, the science of the immune system, and, as you'll soon hear, in explaining the things that genuinely increase your cancer risk, many of which are surprising and the actionable steps that we can all take to reduce our probability of getting cancer. In addition to the usual factors, smoking, UV light, and environmental talks in 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 explored 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. Morrison, 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 Morrison. Dr. Alex Morrison, welcome. And this is the first time that we're going to

have a serious discussion about the immune system cancer and gene editing technologies on this podcast. So, I'm delighted that you're here. It's also great to see you again. Thank you for having really, really good to see you. 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 on the fast track to much better things? Are we, I'm going to slog along for another 10 years before we have cures to

the many concerns that people have about cancer, Alzheimer's and the rest, or are you

“encouraged by what's happening right now? I think maybe there's some, some, the general public”

doesn't quite know how excited biologists are about what's possible. And maybe we've over promised maybe in the past we've said we're on the brink of caring 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, and but going all the way to rewriting specific DNA sequences inside of the cells of our immune system, doing this not one at a time, but testing every gene and understanding pieces of DNA throughout our entire genome to understand what controls ourselves, 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 auto immunity.

And that doesn't just have to be sort of searching for a pill. All of a sudden we can actually talk to our own cells and give them instructions in the language of DNA and the language of molecular biology. And in some instances, this is being done with CRISPR, but it's also being done with lipid nanoparticles and vaccines, and we're still inventing new ways of giving these instructions, but all of a sudden medicine is programming the behavior of cells in a way that's much more

directed than was ever conceivable before. Like there's really a step function in what's imaginable and achievable in medicine. Super exciting. Do you think that molecular biology and genetic engineering and/or AI are the reasons that things are on this accelerated time one? Yes, there's the answer. All of those things. I think we can do experiments at a different level of scale. We can generate

to actually extract insights from massive amounts of data. And you know, I think historically biology was, it was an observational science. If you 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 putting 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 all that 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. Would you mind educating us about the immune system

“that the adaptive in the innate immune system, some of the major cell types, because I think those”

are going to form the kind of building blocks of our discussions about cancer and other things today? Our immune system permeates almost every aspect of our health and disease. It is a system really in the sense of it, it's involved in every part of our body that has evolved to protect us. Largely to protect us against infections, viruses, bacteria, fungus, all sorts of foreign invasions, and our immune system has developed a balance that is, when it's working properly,

doesn't recognize the cells that are supposed to be in the body, but is finally tuned to

recognize signs of things that shouldn't be in the body and to eliminate them. I mean at it's core, that's the basic job of the immune system. To recognize us versus non-oss. 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 as sort of thought of as the first alarm system, that's something 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 and 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 the 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 in 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 in-surface. Each cell will have a different receptor on in-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 we found something that you've been programmed to recognize and program is recognized as foreign. If the immune system is working properly. 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

except based on what exposure to particular pathogens, like why do they make certain receptors and not others? Largely random. Actually, the pieces of DNA at this part of the DNA actually recombine and get pasted together in unique ways. So it's probabilistic. 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 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. That's incredible.

Would you mind mentioning the role of the thymus? Yeah. These days, I'm hearing more and more about we have a thymus and we lose a thymus. Would it be beneficial if we could keep our thymus around? So thymus is actually the reason that T cells are called T cells is the T stands for thymus. And the thymus is an organ that it does sort of shrink as we age, but at least in childhood, it's 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 at largely at random. And then in the thymus, they get called, 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 our, have emerged at random, but then are selected to remove things that recognize your own body targets. There's sort of a negative selection. There's a negative selection. I'll just stuff that's you so that your immune system doesn't attack you, and it knows you from non you. Yeah, that's exactly right. There's actually both a positive selection and a negative selection. That's exactly the right way to think of this

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

“get educated in childhood. Yeah. And that's what you're working with, except that the immune”

system can adapt and make antibodies to things that doesn't recognize. The antibodies come from the, from the other type of lymphocytes. So now, now we can talk about the B cells, B cells are this other type of lymphocytes 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. It would 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. I'd like to take a quick break and acknowledge our sponsor, better help. Better help offers professional therapy with a licensed therapist carried out entirely online. So I've been doing therapy for a very long time, and I can tell you that it's a lot like physical workouts. They're days

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Again, that's betterhelp.com/huberman. Today's episode is also brought to us by Helix Sleep. Helix Sleep makes mattresses and pillows that are customized to your unique sleep needs. Now, I've spoken many times before on this and on other podcasts about the fact that getting a great night's sleep is the foundation of mental health, physical health, and performance. When we aren't getting great sleep on a consistent

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you can go to HelixSleep.com/Huberman, take that two-minute sleep quiz, and Helix will match you to a mattress that's customized for you. Right now, Helix is giving up to 27% off their entire site. Helix has also teamed up with TrueMed, which allows you to use your HSA FSA dollars to shop Helix's award-winning mattresses. Again, that's HelixSleep.com/Huberman to get up to 27% off. What underlies the sort of efficiency and functioning of the immune system? I know I and many

people are thinking, okay, we hear our immune system gets activated. Our immune system is impaired. The one thing that I'm certain supports the immune system is great sleep. 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? I wonder about this, too. I agree, anecdotally. I've experienced that so many times of being run down and then being feel experiencing that I'm susceptible to

infection, but I don't actually know the basis of that. 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 mouth studies, whether we're doing, we're studying largely steady stays, immune responses in mice, and I would say we don't haven't done a full exploration yet of all of the types of ways that general health impinges on the immune system. I had someone in my lab, a postdoc named Sagar Bopot, who came to my lab with an

interest in metabolic health and wanted to study the effect of metabolic health on T-cells.

“There's some sub-growing stuff on this, but it's another, what are the determinants of it?”

He did an experiment in my lab where he exposed something in 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. 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 diet. 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. If we use surrogates that are for the types of drugs that are being used now to treat severe allergy, so we gave antibodies that block allergic responses.

The normal lip diet mice would respond favorably to these. It didn't help that the mice that had the obese high-fat diet response to inflammation, and in some cases it actually may be

“made a worse. I think that there are these systemic ways. 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. 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, you know, are the b-cells engaged more quickly? So they can generate antibodies more quickly? What is it? Great questions. 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

talked about the native immune response, the adaptive immune response. You can see that certain

“genetic mutations that people in Harriet could influence one or multiple branches of that immune”

responses and the consequences that that manifests itself with different types of infection. And I suspect that there's some spectrum of that that you see that you can diagnose the really strong genetic consequences, and then there might be a long tail of poor subtle genetic that might be multi-genic that we don't fully understand. And then I'm sure that there's other determinants of health that are just multi-factorial. And you know, it also becomes this

interplay between the health and then what you get exposed to by your environment. Yeah, 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? I think that there's the what we're exposed to and what we develop tolerance for

“is is critically important during there's some windows of early life that I think 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 more hesitant to expose kids. And I think you can get into these dangerous zones of, 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 is strong evidence that exposure to peanuts can be beneficial. In people who are not yet allergic. What's going on with autoimmune conditions? Yeah. Is this that the the B cells and T cells are at a probabilistic level that T cells developed some reaction? So to speak a binding to cells that we naturally make that they shouldn't know. It just like it happens. I've always been intrigued by by the idea that when the immune system is really ramped up, people will experience

autoimmune like symptoms. I had 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 and like, 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, that and that did the trick. It did the trick. You know, but I was just, 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 it overshot the mark basically. I sort of walked you through it at a first principle

like how things are supposed to work. I told you, okay, there's this process of generating receptors on the surface of T cells antibodies get generated on B cells that they go through this positive selection and negative selection. That's a delicate balancing act and it doesn't actually work that way in practice. In practice T cells escape from the thymus that do recognize our own cell phantigenes and there's actually secondary mechanisms that's to block that but autoimmune

“diseases emerge when those normal checks fail. This and I think it's a consequence that the immune”

system has two major responsibilities. It has to be primed to protect us from infections which would be fatal and be strong and recognize this incredible diversity of potential that 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 you immune system starts recognizing targets in your joints it can cause rheumatoid arthritis.

If it's in the cells that produce insulin and 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

as always these sort of two sides of the coin making sure that we're having strong responses to

infection. We'll talk about cancer where we want to also strengthen our responses. But for autoimmunity inflammation allergies we want to make sure that like our goal therapeutically and with drugs is to make sure that we make the immune system under control and ideally do it in a targeted

do it in a way that just makes you tolerant or not reactive against the things that are being

inappropriately targeted by the immune system. Two things that I'd love to understand about the immune system is how is it that an immune response let's say to a cold virus is systemic like like where is this sort of master control or is it or makes a distributed system that says like 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 piece of wood or

metal and so you're going to get the innate response and you're going to get some pus around it and it would 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 had a like the and I think it's the systemic”

effect that that intrigues me so much like it where is the signal to to to launch a systemic versus a localized response in the immune system how does it determine that? You know I think some of it depends on on what virus we're talking about we have systemically invasive the different viruses can be and some of it can be that the immune system has different levels of you know it can have a local response but the means is the cells that we talked about in the immune system one of

their jobs can actually be to secret things into the bloodstream things that but 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 what can cause the development of fever right so you can have these sort of cascading effects of something being recognized at a particular side of the body

then sending distributed signals to the blood that will make us feel sick and you know in some cases there's again this balancing act of maybe the fever gives us some edge in fighting certain some types of infection but it also makes us feel lousy and so you know the immune system

“is always walking that I think in sometimes the immune system responds to infections is too strong”

and a lot of the the negative consequences will be experienced as the immune system going too far and having to come back as the as an infection gets under control thank you one of the reasons I asked that is well I hate being sick unfortunately I don't get sick too often if I take good care

which I think is like most people I think about antibiotics for instance antibiotics are amazing

yeah I've had a few things where I was like 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 into biotics 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 life or death situation to mitigate the duration or the intensity of some sort of infection because surely your short circling your immune systems 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 second infected

“I don't think so great okay fantastic love that answer love that answer I think you probably”

were exposed and added immune response antibiotics when they're used for bacterial infections

that are susceptible to them are a miracle and you know we live in this amazing

sliver of human history where we have antibiotics that can cure disease I mean I think many of us have had bacterial infections of different kinds cuts and wounds that would have been deadly in other generations and where we're the beneficiary of having antibiotics that work we are at some risk that if we overuse them that window if human history might come to an end if we don't continue to replenish new antibiotics but we gain more and more bacteria that are resistant to antibiotics

are people developing new antibiotics it's an underfunded area of medicine because I just hear a moxasillum plant I have a friend over in the UK who's been having some some eye symptoms that from what I'm learning or 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 about like a hundred years ago we probably

would have just they would have just nucleated the eye which is to be blind right so it's I think they're spectacularly good tool but it seems like there's just a kit of maybe what a five to a

seems like it would be a if for no other reason a trillion dollar industry but also save a lot of lives I don't know whether there's a business reason for that it's a but it is an underfunded area like it's it's not where medicine has turned enough attention and I do think it's a genuine risk alright 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 yeah 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 yeah yeah I mean if anyone's really interested I would highly recommend that this book the Emperor of all melodies which is a which is really a biography of cancer as a disease and talk about I mean

the long history of going back as far as there's records of tumors of various kinds and and the misery associated with that we have a very different understanding of 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 they are 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 cells 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 the cells will then transform into cancer cells they'll start dividing

they'll lose the normal architecture the risk is that they can disrupt things in the in the tissue

where they are or that further mutations can accumulate and they can actually start spreading into

distant sites in the body and that's metastasis when you when you're at when a cancer goes from one local site to another part of the body and as that happens it the those cancer cells it's really

“an evolutionary process where those cancer cells have acquired new genetics that are focused”

on their well-being those cells are dividing they're growing out of control and they're taking the resources they're they're they're growing at the expense of the normal coordination of the human body and that's that's really at its core what what cancer is it's genetic disease where cells lose the normal proper regulation and are dividing out of control in various tissues I can see the picture in my mind where otherwise healthy cell gets a mutation we can talk about how mutations

arise but and then starts spitting off daughter cells yep as it's referred to yep why would the daughter cells inherit the mutation necessarily to then create more cells because that's the proliferation of the tumor yeah certainly cells propagate their DNA into their daughter cells but um I could imagine a situation where every day some of our cells get a mutation spit off a couple daughter cells and then those daughter cells are terminal as we say right and they don't

create more cells is that happening all over the body every day so does this so how is it that the DNA that creates the further propagation gets passed from one cell to the next I do think this is happening constantly it's a process that every time a cell is around especially as it's dividing there is some imperfection and 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 onto 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 and one daughter cell and not the other if that is deleterious if it's damaging which probably most mutations are those cells might start to die off okay something that the

DNA got messed up those cells that are carrying that DNA die yeah they can't take up glucose they can't we they just can't do cell stuff and there's a lot of control mechanisms in the cell to say something something's wrong let's send a program cell death signal to that cell

happens most of the time the problem is if if if that change all of a sudden starts to not be

“damaging but to actually be a signal okay now the cell is is growing more it has some benefit”

that it's accumulated as a result of that mutation now that cell will start to divide more and that that cell that's carrying that first mutation might start dividing more it both of its daughters now will pass on this this mutation that's made it divide more and if in subsequent rounds it gets a second hit that the combination may go from just cells that are dividing a little bit more to cells that take off and become full blown cancer now if there's certain processes that

will accelerate that one was exposure to things that caused DNA damage right the major one is

smoking so when smoking causes chemicals to go into your lungs the the lung cells get exposed

to these chemicals that then cause higher amounts of DNA damage more mutations and just as you have more mutations at higher frequency you're more likely to accumulate the 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 you know will likely have heard of the bronchlor the BRCA genes which predispose to breast cancer and other types of cancer there people start with one copy that's already setting them on a road to higher risk of mutations accumulating and the whole process on and in happens with a higher frequency and so this this March towards cancer cells is more likely to occur in people with

that type of predisposition how common is the BRCA mutation is it equally distributed and men and women yeah what can you tell us and should everyone get tested for BRCA and there's a lot of questions I'll ask them again one by one and then of course we'll talk about things that can be protective and not just but certainly avoiding smoking that would be paramount so how

“common is right in terms of you muted genes like the big ones are smoking sound exposure from”

melanoma you know there are not the balancing features of sound exposure but yeah we can talk about that but clearly UV is is a risk factor for DNA damage in the skin I mean all we're really happy going on regular my the things I've said around sunlight been contorted so many in the woods is a pretzel twist now no it's more like one of those balloon animals at a party but it's not it's a mess the too much UV is bad for for skin cells it's just bad you need

some but too much is bad long way of life light is great for and they're in lies the challenge yeah but yeah most sunlight but you don't want excessive UV don't get a avoid getting sunburn 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 they're 50 and you know just a little bit older than 60 and the other and you know brutal

especially when you you know one of them I know their kids and you know it's just for young people getting cancer and I know their childhood cancers but BRCA seems pretty common I don't know the numbers on the top of my head I mean they're not the major like numerical causes of cancer in the scheme of cancers that develop it's it's it's it's it's it's it's

minority it's a relatively small set number of the full set of cancers the problem is if you

inherit a broken mutation as an individual you have a very high risk of developing cancer so it as an individual your risk goes way way up and of certain types of cancer in particular and we can all get tested for it now pretty and yes 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 it's 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 develop breast cancer the ones who did develop it there was a thought well maybe there's an underlying genetic prescription and that helped identify those genes interesting everyone get tested you know because there are lifestyle factors that can reduce your cancer risk I'd like to talk about mutagens yeah smoking bad I'll go and 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 is like beyond me but okay teach their own environmental sort of and workplace hazards you know like known mutagens you work in a laboratory

yes there's always worried me working in a laboratory there are a lot of

carcinogenic chemicals in a laboratory for good reason yeah yeah we're we're trying to study cancer but we're certainly working around a lot of things they could cause cancer yeah chemicals radiation yeah I don't know if you better you I did a lot of a lot of experiments radio labeling cells yeah I mean we well fortunately we worked with you know radio tagged amino acids with radiation that was we were told and I do believe was not not as as dangerous as some of the others but yeah I mean

that kept so chemical exposures are a big one yep and so those those labels on paints and thinners and stuff in the garage that's real because that's a real thing they mutate cells

“and there's you know there's some spectrum of sure stronger and less strong ones and I think”

oftentimes we're operating in an absence of great data but I you know I think there's a lot of things are implicated as potential mutagens pesticides yeah you look at cancer rates in in rural areas near where you know crops are tested with pesticides and we've had Seanus one came on here and she's like listen you know that the cancer risks the you know endocrine disruptor risk we think of it's like big cities as dirty and dangerous and they are for certain reasons but she said

if you really see the spikes in in these cancers relate to environmental factors it's less so bus exhaust than it is pesticides I mean it is not evenly or fairly distributed there's some people get exposed way more to these things and we haven't studied them enough we need we need way more study to really be able to answer okay and and and people shouldn't be left

this might just me just speaking isn't 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”

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and a bottle of vitamin D3K2 with your subscription. I get x-rays at the dentist now and again but I prefer not to get them x-rays cause mutations. Again there's a trade-off and the dose sure. I you know when you need an x-ray you need an x-ray but I wouldn't do them for fun. 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 level exposures and we know pilots and this is for other reasons because you know you can tell us but atmospherically they're exposed to more radiation cancer rates are higher in pilots now they're sitting a lot to prostate kids okay there's a

“bunch of things there but do you yourself avoid the scanner at the airport? Honestly I do but I can't”

say that there's data for that. I feel the same way as you like if I could avoid it I try to minimize but I that's not based on some inside knowledge I have but I have the same bias of sure yeah less seems better yeah I mean I'm not out to get the scanner industry. I think it's useful for people to hear that that you could that one can have no formal data yeah but an understanding of mechanism that leads them to to hedge yeah it's good to know are there any um mutagens and

well is a carcinogen and a mutage in the same thing so they're they're closely related mutagen I think means that you're mutating that you're changing the DNA in the cell that's

that 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. I love barbecue meat I don't like barbecue

“sauce but I like meat with a char yeah is the char bad I think so I mean I like it too but yeah”

yeah yeah again these are balancing decisions in life sure but yes yeah there there there there's some there's I mean meat in general has been implicated as a potential carcinogen especially even color rectal cancer there's some data around them yeah my read of those data not the char data yeah but the the meat data is it's tricky um from this is just my standpoint I want to make sure I put brackets around this that this is my ownership read of the literature is that

many of the studies that looked at meat-riched red meat-rich diets versus plant-based diets

the problem is a lot times the red meat-in-rich diets had a bunch of other things in them

like sourcing was in consider there was also a lot of um starches like is it because nowadays you find people who seem to at least feel better who knows about the longevity aspect feel better eating red meat fruits and vegetables it limited amounts of starches versus so I feel like the nutrition studies are a mess they're kind of a disaster yeah yeah don't have clarity on the

“lesson yeah yeah and then it seems like it changes the the the direction I think some things”

we have pretty good common sense intuition about fiber yeah old ultra processed foods are probably bad like you know but I think the balance of exactly what whole foods were eating probably still needs to be worked out how do you think about the data um on like for instance food dies is very timely yeah where a certain food die yeah at a very very very high concentration in laboratory animals yeah creates a significantly higher incidence of of tumors and cancers in

those animals yeah but then the amount of food die that's in the human food is is a tiny fraction of them yeah I'm not trying to get political here I just think as a framework for people to think about there are many carcinogens I'm sure right in this environment I don't doubt that the lacquer on this table in fact if that's even what they used um if ingested could cause um could cause cancer I don't doubt that right but I don't know that in its in its form here

being near it for many hours a day does that I doubt it we're not inhaling the table this is what I mean by this this this this level of confusion I think we all live with this background confusion of the thing some study has been published in in my he said whole 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 and sure there are some combination of things that are increasing our risk of cancer 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 you know they know smokers who don't get lung cancer yeah and non-smokers who do and non-smokers who do and so I think people go well like what they

actually has caused I believe a lot of um damage in the faith and in medicine unfortunately because the messaging is all uh is mixed up yeah I think that nowadays people are trying to do what they can to protect themselves but people still get cancer you can do everything right and still get cancer is that even if you don't have a brak of me actually absolutely I mean absolutely you know I think the the last thing you ever want to do is like it's tributes

someone's actions to to cancer I mean it is it is a probabilistic disease where some set of mutations occur that cause a really devastating disease and so 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 how do we handle how do we treat cancer when it comes up and this is where these two conversations that we've been having really come together of talking about the immune system

we went through a lot of I think it would be actually we went through a lot of sort of detailed mechanism thinking about the different cell constituents of our immune system I will tell you that when I went to medical school which wasn't that long ago I graduated in 2010 the dogmo was don't waste time thinking about cancer immunology cancer immunology is a field that's going nowhere I mean I think I was embossed and I think that was maybe there was some local bias in that

direction but this was not the mainstream of thinking about how we would treat cancer at that point that the way the cancer was being treated was chemotherapy which you know it's 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 to the healthy cells and ask people to endure all the side effects

treatment we all want to do better than that it's very unpleasant very very unpleasant unpleasant

“and worse I mean I mean people endure heart you know it's we put we put people through”

horrific things because it's the best we can do and then there was a wave of thinking okay well let's try to make drugs that are targeted to the mutations that we talked about and that was that was the hot thing that was for the promising avenue when I was in medical school of like okay now we we've really measured that these are mutations that accumulate inside of cancer cells this is what's causing cancer let's let's make drugs that go after those things and

turned out that that was although a lot of good has come from that people have extended lives cancer is a way of working around that and so these are cell cycle inhibitors signaling things various mutations affect this 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 yeah I think that benefit has come but cancer has ways of mutating around”

that and could be developing resistance the same where we talked about resistance and bacteria to antibiotics if they're exposed you can cancer cells are can evolve quickly and can become resistant to these targeted modifications what has emerged as a whole new way of thinking about going after cancer is using the power of the immune system that we talked about at the beginning and redirecting that against cancer targets this has changed how we think about cancer treatment

it's the hope is that we talked we talked all of us have this immune system that goes through every organ and our body it circulates we've weight 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 that are immune system we 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”

this cell should be here this should not if we could get that level of precision where we can 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 has 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 there are immunotherapy drugs a lot of people will have heard of these things pd1 ctla for or 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 break on the on the t cells the t cells go stronger and they can be unleashed against cancer just by taking the breaks off of them what sorts of cancers has the successful 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 it was cured amazing and so you know that 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 that has changed how melanoma is treated it's in other cancers to varying degrees because some types of cancers can respond to this that's taking the drug that unleashes the t cells that are already in our body the focus of my research in it is well first thing I said it was we're living in this amazing moment of biology where we can we can do things to cells in our body

that with incredible precision and and we're often just limited by our imagination and what we can see now is that we don't actually have to just be limited to the cells that the t cells that are natural 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 in 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 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

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 re-infused 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 in 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 was the first pediatric patient to be treated

“with a carti-cell for for cancer so she she's become a heroic figure Emily Whitehead she was I think”

eight at the time and she had a form of leukemia that had in response it just was for some reason whatever reason it failed all the treatments and it just nothing worked she was going to be sent home on hospice she had exhausted all the possibilities at the age of eight and she got enrolled at that time highly experimental treatment to get these carti cells so her blood cells were taken out in a big blood donation her to own t cells were genetically modified we could talk

about how that was done it's actually done with a pretty crude technique that's been around actually used viruses lente viruses these are sort of modified each IV viruses to deliver this extra piece of DNA that encoded the car and this was done on her cells and then after that

“extra gene was put into the t cells the t cells were re-infused into her body and it was not a”

straightforward course she she ended up in the ICU the immune system had we people 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 us on the her cancer cells disappeared amazing and the lente virus itself didn't

spark an immune reaction that was that outweighed the benefits of the cargo no is amazingly it really hasn't I mean there's there's been some discussion about the risks of using these lente viruses and we will talk in a second about how we could do better now 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 add-in know which is like a cold virus or lente 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 they're a shuttle it's an amazing application of biological

understand right that all of a sudden we've been studying viruses because of the risk that they have we but we've learned that they can deliver that that viruses have evolved to be very good

“shuttles and to deliver their genetic material and to cells the way I think of it that is the viruses have”

evolved to take advantage of our biology and our genes and so we did the ultimate to shea in these instances like you're so good at hijacking ourselves DNA and proliferating all right we'll leverage you so help us as opposed to hurt us right that's exactly right and so that was done in 2012 Emily Whitehead was eight it was done as an experimental treatment at the University of Pennsylvania and the story now is that now all these years later Emily Whitehead is not only cured of her leukemia she's

premed at the University of Pennsylvania so awesome and so awesome so no one could ignore them you know this was this wasn't this was just all of a sudden this dogma that I just been taught a couple of years early in medical school that we should ignore the cancer immunotherapy it was just we were just wrong and all of a sudden the field woke up and said okay the immune system is not just limited to treating the viruses and back to protecting us from very viruses and back to the immune system can

be exploited and potentially re-engineered to protect us from cancer and maybe other diseases so that was 2012 2012 also was the year that a paper got published in science by a manual sharp on TA in Jennifer Doudna that introduced this new technology called CRISPR and we can we'll 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 that was looking around and trying to figure out what my lab would do and all of a sudden I was arriving with a empty lab space at exactly the same moment that the world was shown that T-cells could cure cancer and that we had a tool that could potentially rewrite DNA

best tools we had at the time but pretty clunky and non-precise and 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 and to being able to now take CRISPR technology get it to work in T-cells to learn the rules about what are the genetic changes that will be most effective at making T-cells into into immunotherapies, the 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 we're at these CAR T-cells if 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 we can talk about that but getting T-cells to find the right targets in tumors and then work inside of tumor environments which are inherently immunosuppressive requires figuring out additional gene edits that are now possible with CRISPR to try to beat the cancer at its own game if cancer is evolving to make itself cloaked from the immune system now with CRISPR we can think about getting one step ahead and making T-cells that are able to

“be resist all the tricks that cancers throw at it to be more and 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 amazing just amazing in the story of this young woman is

spectacular I have two questions before we talk about CRISPR technology yeah 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 just have the major issue of chemo and radiation therapy but the first question again was you why more

mutations as we get older so I think there's a few cancers that peak in childhood and there's should risk as the body is developing of certain cancer childhood cancers and there's childhood leukemias for example then that like when we talk about Emily Whitehead but most cancers as you said exactly as you said that there's this sort of increase and there 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 the cells that have the mutations will die off and it's just a game that unfolds over time and the more time you have cells dividing and sticking around on the body they're accumulating more damage and eventually you're more likely that that damage would actually transform the cells into a cancer cell so time is is is is a big factor here time and just to accumulate a damage and the other

question was you know how is it that the lente virus knows to the lente viral cargo carrying T cells no to attack the cancer and not something else so this is a key question for the field right is and I think one of the things that worked incredibly well was a brilliant choice by a group of

scientists and different few different places that converged on the target that was used in the first

car T cell and what the target is known as is a protein called CD19 that's just the name of this thing that's found on a lot of different types of B cells so this brings us back to this discussion the the leukemia is themselves are a a cancer of the immune cells so they're cancer of B cells and CD19 is found on the on the surface of many a large number of different types of B cell

“leukemia is a lymphomas I see I think one of the things that turns out to be serendipitous here”

is that B cells themselves natural healthy B cells actually also have CD19 on their surface what just turns out to be serendipitous is that the body can tolerate those cells going away and so what is 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

leukemia cells they're they're they're getting collateral B cells but by and large to a first

“approximation people can live without those cells and so that side effect has just been tolerable”

finding that balance gets harder and harder for more cancers right if you start to think about pancreatic cancer brain cancer finding targets that if you hit the healthy pancreas or the healthy brain are not toxic it's it's harder and harder so people are thinking about more and more sophisticated ways to look for these targets that are selectively found on the cancer cell and not on the healthy cell or to think about ways that you might actually make the cell depend on

recognizing multiple features so that you can have what sometimes talked about is like a two factor authentication like the T cell will only kill cancer if it finds this and this and that combination of things are not found on healthy cells even if one or the other might be so people are thinking

“about how do we get more sophisticated about building these discrimination systems into 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 awesome before we talk about CRISPR there was one other question that I know many people will be thinking about a few years back a five ten 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 so and of course this is the way the internet works but I did see some papers in some decent journals you know that at least we're exploring this so our low they're just low car what's called what they are ketogenic diets have they been shown to be useful for treatment or avoidance of cancer

I have to defer to you I actually I don't I don't know the answer that yeah okay my guess is that people are still looking at this but you know there was also the idea that they could be useful for certain forms of dementia there was an effort to call dementia you know type three diabetes but my understanding from talking to the experts and 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 uh called a sack 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 yeah it's here it's powerful it's scarce certain people it excites other people

but most people don't know how it works because there's really no incentive too but I think the story of CRISPR is actually also a story about how science works yeah and that's important too I think it's exactly true I think it is a perfect illustration of something where a discovery happened with that no one was planning but changed biology let me tell you the story in two separate arcs one arc is the arc of understanding DNA you know if you go back to Watson and Crick it's understanding

the double helix to understand the structure of the DNA sequences that mature as we've learned had a sequence to understand to be able to measure a row of ATs and Cs and Gs that whatever combination they are will start to be the building blocks for programming which proteins get made inside a cell and then around 2000 we get to the first draft of the human genome which is this

multi-billion dollar project across the world to come up with a draft of one human genome sequence

milestone for biology and medicine and then DNA sequencing technologies continue to improve and cost comes down we're going to the point where we can start to measure big chunks of our DNA increasingly affordable costs and people we're 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 is maturing we're desperately looking

happens if you change sequence and people were stumbling around looking for different tools there

“was there was a range of these things there were zinc fingers they people lente virus 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 and cells and it had been a longstanding effort out of nowhere emerges CRISPR as the answer to this problem CRISPR was being studied as an an interesting and unusual set of DNA sequences that were found in certain types of bacteria they were these repeated sequences and no one knew what they were and people out of real basic curiosity about what was happening

in bacteria started studying these repeat sequences and what they were doing and little by little it was worked out that these repeat sequences actually form 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 trying to kill everyone else and so bacteria are constantly being bombarded by certain types of viruses they're called bacteria phage viruses and they've evolved a series of bacteria have developed a series of defense mechanisms to protect themselves from from these viruses CRISPR turns out to be a bacterial defense mechanism against viruses

which is kind of amazing that this this thing that is entered into popular culture is a bacteria

protection against bacteria phage now why has this caught the world of biology by storm well what was realized was that the way that that CRISPR works to protect against itself the protect bacteria from viruses is that it can recognize particular sequences of DNA which are virus sequences and discern we discriminate whether it's a virus sequence or it's 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 a Jennifer Dowen and a manual shop a shop and DNA 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 this CRISPR system that had evolved to protect

bacteria and the same rules that allowed bacteria to scan across DNA and find a virus sequence and cut it could be used to scan across any DNA and cut at a particular sequence that's the power of CRISPR now why do we care so much about being able to cut a particular sequence if you can cut you can also start pasting you can cut out genes that are limiting that you don't you don't want to be in a cell you can start pasting in sequences to replace mutations that cause disease

we can start pasting in big sequences like the sequence for cars or others that types of things

that will make T cells more powerful so and this is I'm focused on T cells but this is now

in every aspect of biology people are studying this in plants and to make crops that will be drought resistant people are studying this in 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”

is 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 the 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 so this and and what's so special about that is that we actually know with perfect near perfect precision the rules of how an RNA will recognize any DNA sequence

so you can now cut DNA sequences at will and it's gotten to the point where now if we want to cut

“a piece of DNA we order a piece of RNA off the internet it shows up in in 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 was came out in 2010 and all of a sudden you can go on the internet take a place in the genome that you're interested in studying order a piece of RNA make your your targeted CRISPR molecule and make a cut or cut and a paste at that particular site and then in a very tangible way

read out the consequences you're going into the source code of DNA inside of a cell and you can when you make that change you can say what what happens to the cell is it is it's a stronger response is 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 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 if the related question is if you're going to introduce a gene sequence there

“how do you ensure that there aren't downstream effects I mean I think what you're getting”

out of 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 all right so I think we've done a lot and the field has done a lot of work to test off targets right if you're programming to cut on one place on chromosome six do you actually evidently accidentally ever cut anywhere else and there's a range sometimes some sequences are a little bit more promiscuous than others but we've got

in quite good at getting more and more precise to say okay we're making these high fidelity cuts that at one place there are still the second risk of bystander effects okay you make a cut what does the DNA get chewed back and at the neighboring part there's been in some extreme places

“of chromosomes actually falling off I all these things can happen and I think what we're kind”

of at a place in a field where now we're thinking about for each disease of risk benefit of okay

there's going to be there's always a risk for any medicine of some unintended consequences

we have to be on the lookout for them we have to know what what they are most cells as we said that get a mutation don't have a problem they just die off so if you have an unintended consequence most will die but there is always the risk of the unintended consequences and I think as a field we have to be humble about that that said the the the CRISPR world is not static and what I took what I the story I told you was like the building block of CRISPR it's a protein

scissor that can be targeted to any piece of DNA within RNA molecule people are appropriately thinking well scissors can cause damage maybe that the CRISPR molecule should actually be re-engineer 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 Lou 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 demonized domain something that will change DNA nucleotides when it's recruited to predict a place and 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 it can be a stable program of things getting turned on or off without any change in the A's or T's and C's and G's and now we and other 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

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potassium are vital for the functioning of all cells in your body especially your neurons or your nerve cells drinking element makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes my days tend to start really fast meaning I have to jump right into work or right into exercise so to make sure that I'm hydrated and I have sufficient electrolytes when I first wake up in the morning I drink 16 to 32 ounces of water with an element packet dissolved

in it I also drink element dissolved in water during any kind of physical exercise that I'm doing

especially on hot days when I'm sweating a lot and losing water and electrolytes element has a bunch of great tasting flavors in fact I love them all I love the watermelon the raspberry the citrus and I really love the lemonade flavor so if you'd like to try element you can go to drink element dot com slash human to claim a free element sample pack with any purchase again that's drink element dot com slash human to claim a free sample pack I'm curious about getting crisper into the cells

of interest yeah you know the lentivirus example that you gave before 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 um I could imagine a surgery where you inject directly into those organs but uh one to be wonderful if you could um get the cells of interest from you

know without having to be so invasive um so what's being done there in terms of trafficking um crisper to appropriate cell types or indoor organs and then that sort of seeds another question that I'll hold off on about whether we should be banking uh cells or uh for what's coming

first of all I just want to pause this this is great I love this conversation

I do too I mean you're taking us to the the I don't like the phrase bleeding edge in sounds of island but you're taking us to the cutting edge of molecular biology and medicine and we are peering over into what's next like what your children and my children and are probably our parents also will uh be able to benefit from in the next 10 years maybe sooner yeah we're really talking about things that are happening now and and happening at an

“accelerating rate so you asked part of what just got made me have that reaction 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 tell 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 Carti 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 a human blood sample that are not immortalized that can only stay in a dish for a short amount of time and still retain their function and I put a I sort of tripled down on this was 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 Dowdna through some persistence on my own and Jennifer Dowdna and I sat down and started thinking about how could we team up to take her expertise in CRISPR biochemistry and get it to work in T cells and we settled on this this thing that was not at the top of my list of things that would work but ended up opening up the field we actually purified the the CRISPR protein so we had protein and RNA that would we we could make in a

test tube now we now we ordered 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 use this trick that's been around for a long time knowing as long as it's been around sounds magical and no one quite understands how it works

we put this cells into a device that gives a small electrical current to the T cells electroporation

I don't do it anymore um electroprated a lot of brains of of intact animals yeah you inject DNA

“it's floating around in the in the local tissue you pass some square wave current yeah 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 a transfected and sometimes you end up with 40,000 cells transfected it's a wildly useful technique it but it's a little bit hit or miss. That's perfect description

and so we we's my first postdoc in my lab Katherine Schumann sat there and tested different

electroporation conditions altering these little postdocs well also long calls you're taking me back to my graduate and 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 not kill the cells. We we're walking this tight rope 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 you know and we did it and we've worked we've optimized this and

“it was one of those things you when it happens you you see it and you just realize it's it's binary”

like all of a sudden you're you're editing DNA inside of of T cells and you know we got our foot in the door with some level of efficiency we've gone through the roof this is now used by labs widely and it's incredibly efficient and some cells die but overwhelmingly end up with cells that that are gene edited it. She figured out the protocol. She really did and it's been optimized and then

another grad student 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 were just changed a couple of nucleotides at a time our mindset was like maybe we can fix a mutation and individual mutation. Theo said let's not stop there let's put big piece of DNA and we've pushed this boundary of being able to say let's

“pick a site make a cut and introduce hundreds or up thousands of different nucleotides to people”

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 it's in it's clinical third clinical trial right now for a solid tumor is it's in a clinical trial for prostate cancer that's about to start at rolling patients and that company can

now do this at industrial scale it takes patient cells electreparates them and has now written a long piece of like ten ten thousand nucleotides of DNA code that put in a sequence of a combination of different receptors including a car and additional gene enhancements that will

make these T cells more powerful and in a tumor micro environment and then they go into the blood

stream 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 that's exact a bolster the healthy cells to bolster the the the T cells that carry these receptors on it to make them persist a lot every both are exactly awesome that's happening and you know the that the way that that happens is that 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 that the electreparation 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 they're the cells are then thought 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 the cells that have been modified by the CRISPR Casino and they're sitting in this bag they get infused are they designed is the CRISPR designed to to only go after the prostate cancer cells or is there some version of this where you can enoculate against a number of different cancers in other words come understanding correctly if they're sort of canonical mutation sequences that occur in all

cancer cells is there a version of this where I give some blood you or a company probably company electreparates them with the CRISPR Casino system brings in resilience genes for the T cells for my T cells plus some attack genes that are going to destroy the cancer cells and then

all cancers that probably are forming at multiple sites throughout my body low mutations here

low mutations there hopefully they don't you know proliferate but is there a way to just

“short-circuit cancer body wide I think that's a hope that all of us have to some extent I think”

these technologies get proven out in patients who where the risk benefit of the unapproved technology is tolerated and you know 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 for that that's where we start but our hope is that these technologies eventually will be proven to be safe because they'll get more and more precise I hope

the cost would go down and I don't know you know you talk about the other extreme of doing a preventatively but at least we should start marching earlier and earlier in the course of diagnosis and the hope is that you know they'll be there 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 central

life's factory and electreperated although that's been incredibly powerful and it's not stopping now we're actually starting academically in my in an institute that I run the Gladstone UCSF Institute of Genomic Immunology we're starting 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 and in these targeted ways with electreperation 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 hard or neuroscience right for different diseases um and that is a field that is now exploding thinking about technologies it's another area where there's just tools that are are happening so fast you know when I was postdoc there was it it was all about it seemed for a few years like different ways to get genes into cells yeah um so there's electreperation there are lengthy viruses there are had no viruses there

um calcium phosphate transaction 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 um customized liposomes like little fatty bubbles because fatty stuff can get onto and through cell membrane so it makes good sense but but with some sort of zip coating so that you could inject these fatty bubbles um or swallow them even get them into the bloodstream and then those fatty bubbles would go to the very

specific type of liver cell or brain cell that you wanted has that technology moved forward at all that liposome technology dramatically oh great dramatic relief to her and relieved to here 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 electreperation now no viruses works spectacularly well for my experiments but a lot of people needed cell type specific in um

transaction yeah through a vein injection so all of these things have gone under rapid progress the virus talk with the viruses we talked about viruses as a tool to do as a shuttle of DNA they naturally each one will have some range of what cells it would in fact this is for a virus this is this is called tropism what is 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 that 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 try there's still problems 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 protein to a cell that's specified by what that virus tropism is and that and people are working on engineering these tropisms with a lot of

SSRIs of all these side effects well that's because you're getting serotonin you know increases

“at locations you don't want it like that you could imagine only getting drugs to certain cells”

so it's super to me it's super exciting and just seem so fundamental so I'm relieved to hear that there's there's progress being made anything that can be genetically encoded you can start imagining these types of targeted now you asked about lipid lipisomes now lipisomes have kind of come up with our new name is lipid nanoparticles and nanoparticles and it rolls off the tone nicely and you know with the abbreviation we use as LNPs but

billion people around the world have now been injected with LNPs LNPs are the technology that

delivered mRNA vaccines okay that that'll raise to my brows it yeah no we're going to talk about vaccines listen we're going every we're we're going into it all today they were liposome bound these essentially 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 describe so they go to particular cells if you inject them into the body lipid nanoparticles

naturally tend to go to the liver so people are using these already to cure genetic diseases that were 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 America that we were able to develop something on a short timeline to address”

so a pandemic that was killing people but I understand this 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 like if people would have whatever work all of a sudden it could be manufactured at scale could deliver a synthetic piece of mRNA to give a temporary instruction to cells to make a protein to protect us and whether that's for COVID or for other things all of a sudden where again I 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 much like totally different we're talking about delivering CRISPR it's not the NMR and A 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 so 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 the disease little fat bubbles exactly as you said but in them they they included an 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 it would encode a car these artificial receptors against cancer and they've done this now in testing in a number of models they could actually make these car T-cells by injecting lipid nanoparticles into the body without ever taking the T-cells out of the bloodstream

“I think we're going to see more and more things like that from the farm industry as 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 effective at getting to the root cause of disease 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 divide 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 that was a major player right people especially Americans don't like to be told what to do that's just I've noticed that 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 just haven't I'm not trying to

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 I'll answer this specific question but I think the context that you give is also

“really important part of this and I want to take one second to talk about this I think to”

to answer your first question we talked about DNA is the sort of source code we talked about

proteins is what the DNA is ultimately encoded let's just talk for a second about what mRNA is mRNA is the sort of temporary intermediate between those things DNA will get what's called transcribed into mRNA which is another nucleic acid but doesn't stick around permanently it is the temporary instruction which will then go to the ribosome and become the template the template for a particular protein the idea of an mRNA vaccine is that you're using this temporary template so that

the cells that will take this up will make proteins from this temporary template for some period of time

now there could be so I you can always imagine the extreme outliers of ways that this could last

longer or not but fundamentally this is you're you're putting in an mRNA that gives a temporary instruction to the cell to make a small part of the COVID vaccine now 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 and you know that that so there's we're talking about genetic material making mRNA either way whether it's the mRNA from the COVID or a design small part of

“that COVID vaccine that if that COVID genome that we're using is a vaccine so I think it's important to”

think about the risks and the context of the virus versus what we're doing with it with a vaccine so I got the COVID vaccine enthusiasticly and I and I actually I think overwhelmingly my you know I mean I know overwhelmingly my immunology colleagues to the same in people who live in this world if immunology a great enthusiasm that this could be done in built now what that doesn't answer what you said about the cultural phenomenon I'm talking just as a person not an immunologist please

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 shut down shut down of economic life shut down 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 we're 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. Well I spend 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 on both on the science and the the regulatory side to get vaccines approved in an extraordinary time line taking advantage of a number of technologies and making them all so I was watching this the science unfold with some some optimism but also watching the trust in science being eroded I developed it aside hobby which has I've been I've just gone back I've been reading I've been reading presidential biographies

sequentially and this is this is just a side hobby. Now in this reading and thinking about this sort of frustration with how science was sort of tearing things apart I fell into this sort of strange relief in reading about early American history in 1793 there was a yellow fever epidemic in in Philadelphia and actually the early parties that were forming the the federalists and the Democrats actually took like wildly dissenting views of how to deal with an epidemic they had different

that at that time the Jeffersonian Democrats were in favor of like really extreme bloodletting techniques

and the in 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 in that these discussions of how we deal with infections”

which are inherently societal diseases on earth 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 and any decision of how we deal with thinking about the trade-offs that we're willing to make in the face of of a pandemic or an epidemic. 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 yeah I love his books so how do you select the author of each biographies? This is a project that I spend a lot of time each one I go through a period of indecision about which one I okay I should read I can share my list okay I'm not I'm not done yet and this has been

“over several years I've been I'm now up to World War II you should do a podcast some day”

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 learn anyway awesome 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

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functionhealth.com/huberman to get early access to function. I have a question related to technologies to killing or altering cells that we didn't cover but since we've touched on a number of them the banana particles lenty viruses since we're 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 support and 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 it's support and will kill you if it goes systemic but the idea there is that you take the support and 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? 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 right you have a targeting component you have in the in antibody is a natural one where

something on the surface of cancer cells. People have then developed what's called antibody drug

conjugates or basically a drug or a taco 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 when people are now trying to attach radioactive isotopes there's radio ligand 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 that the when I've talked about this car or 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 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 engages 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”

bicep specific 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 an 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. 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. I'll push a one step further. I'm actually helping to organize a cancer immunotherapy conference here in LA I'm simultaneously here for 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 this talk was an amgen's been one of the leaders in these bites I think they actually”

trademarked this idea of bicep specific T-cell engagement. These are antibody fragments but one of the leaders at amgen talked yesterday about how looking forward these are being used as just traditional antibodies that come out of animals but they're actually being used as AI designed to protein and gager as if 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 of one of these Lego blocks for these modular multi-multi-faceted cell end gagers or drug end gagers or any of these other things so is another area where the the cross-talk between experimental capabilities and computational

capabilities is further accelerating what's possible. Incredible. Would you mind if I asked a

couple of questions about the kind of science sociology and ethics around CRISPR? No I thought I would love. 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 cast experiment on babies. Yeah. I don't know when he

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 is a pod cast or 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 him throw him in a cell or give him a Nobel Prize.

It was like there was this kind 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 you know what he had learned at Stanford what was done at Stanford and 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 have heard about him or 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. 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.

“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 the scientist got up and announced with extraordinary pride in one of the sessions in this conference that he had done at he had done genetic modification of embryos and my understanding of what it happened was that there were two twins who were parents who wanted to have kids and the father was HIV positive and the modifications that they decided to try to make were to

delete a gene that is if it's deleted can confer resistance to HIV. This is a gene called CCR5. There's people who naturally have a certain mutation in this. It's some frequency and mutations in this gene confer resistance to HIV if they're naturally occurring. So that was the supposed rational. So it was a disease aspect to it. Okay I wasn't aware of that. Thank you for that clarification. 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. If through sperm washing and things that can be done that would for my understanding essentially reduce the risk to near zero of transmission

“through from a father to an embryo. So I think it was a bit of a manufactured need. But there was”

the supposed 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. 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 with this father's sperm. There's the mother's eggs. They created multiple embryos and then they delivered CRISPR into these embryos and trying to create mutations in the CCR 5 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've no less about this but there were also series concerns about the way that consent was done and how much was informed about the actual benefits would

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 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 understood wonder what some period of house arrest. Okay he do he wasn't on it. I believe so after I think after there was some degree of scientific outrage at this moment they lasted maybe a week or two okay well you're clarifying a lot of the

“and the important detail. 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 mean I'll tell you now what I think yeah please. 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. You know I told you I dedicated my life now to creating CRISPR technologies to engineer individual cells in the immune system but these are what we call somatic edits 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 those edit were not making genetic edits in sperm or in eggs. If you do it in an embryo all of a

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 you know maybe you want to add you know genes that would make people be more muscular or will there be a rush to you know or enhance memory 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've got 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 and a sub region of the hippocampus

“the idea was they were trying to make super smart mice I remember that was that made quite a splash at”

the time I forget where that went maybe Joe followed up on that I don't know but but that would be the sort of thing that people are both excited about and concerned about you know could you confer your offspring with better memory genes yeah but of course we have no idea if that's a good or bad thing forgetting certain things is very useful as well I completely agree with you I think the point you made is a key one that we do have a what we do live in a world where people

do IVF and we do pre-implantation genetic testing and we select people the option to select not implant embryos that have certain mutations that's already a level of like avoiding disease in an next generation if there's a severe mutation I think it's not it's it's a qualitatively different step to then not just select but to actually make a genetic change all those are now you're really hampered you're you have the ability to make some kind of mass produced genetic

edit and many embryos I worry a lot about what this means for our offspring if they are designed rather than just born by by chance I worry about fads you know when you think about like 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 get an order of those in in concert with IVF and I don't think we gain enough

to to come close to what we would lose a society if we embark on that journey of of editing offspring appreciate the clear stance and an 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

“this is an important caveat for deep sequencing embryos from IVF so typically with IVF”

check to see that their chromosome only normal that they're you employed as they say and they'll do some sequencing in the of the parents maybe of the of the embryos as well for certain mutations but there's this whole other industry now you believe a company in the Bay Area or kid is probably the most popular one or well-known one where if you pay a certain amount of money they'll

readout of potential disease genes and and I've looked at that technology and they're very clear

that they're at some point they can't draw causal relationship between say like a neurologin mutation and autism but they're these implications based on the animal data or and so it starts to become this it's not gene editing yeah but it is a deeper and deeper gene sequencing based selection of embryos yeah first of all I'm I'm sympathetic to the idea right like we we we we want to protect our kids from from 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 abnormality”

that would really impair life span or quality of life for your offspring I the input impulse that we know that's this this sort of straightforward chromosomal testing that's done from the first level of you does we'll miss a lot of mutations so people I understand the idea of trying to fill that

in with more deep sequencing or comprehensive sequencing of the genome the problem is there are

some mutations that if we know if we see them we will know that they can be caused severe disease but there's a lot that are 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 just so it's not an access that actually exists there aren't categorically more desirable or less desirable that we want

diverse diverse people for and you know how successful you're going to be as an interplay of like 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 there's it introduces a false”

access there's another book that I would would recommend here that I read years ago and I actually probably overdue to go back and reread this this predates CRISPR technology but there's a Harvard philosopher Michael Sandal 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 like a part of our relationship with with our kids with ourselves of thinking okay this is this is the human experience of your product of some degree of chance and circumstance. I'll definitely check out the book I know the whole point of life is not to be a quote unquote 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 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 it is now and are now grateful for. I know of no exception to that it's just kind of it's of the story of humans in many ways it's the story of humans in fact a people who perhaps are told that they're perfect in every dimension their entire lives they I can only imagine the amount of pressure they must feel in

fact before today's discussion we were talking about people that we knew that perhaps had been told that

“and some of the fragility that that can introduce to the psyche. I think that's really well said I”

think it goes in both ways I think things that we think our hardships or our disability is often end up being the things that that make us who we are and you know make us more sympathetic give us to add a depth of humans and the things that we think are things that make us perfect are the things that are really holding us back or creating all sorts of false ideas that limit us. I come to green more. I'd love to know what right now you're most excited about

for your own intellectual enrichment and in your lab and like what you really feel it's like the thing that has the most electricity for you and and if you're willing to also give us a hint of what's

just right over the edge in terms of what you think will be the next big therapeutic breakthrough

that we can look forward to. Thanks for asking that. So I'm going to give a little bit of a long, please. Entering answer to that. I mean listen when it comes to me you don't have to succinct is not something that is sort of like exists in my neural circuitry although I try.

I talked about a biotech if 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 haven't even talked today but we haven't fully talked yet about the idea of CART cells for auto immunity. We left that open a little bit but

that's an amazing moment that we're at right now that the same CART cells that are being used to

get rid of b-cell leukemias are also getting rid of b-cells which are contributing to auto immune disease. So without making any change people are already starting to see incredible responses in the early trials for lupus and other auto immune diseases with t-cells engineered to eliminate b-cells. Fantastic. Could you just mention a few other disease targets? I know a few people with fiber myelgia. They suffer tremendously. Fiber myelgia is a disease that we just don't understand.

“Like that is that is to talk about understudy diseases. I think fiber myelgia is something that”

gets bucketed in a certain way and we just have not figured out what is what it really is. What

would cause is it. And so that is its own thing. But for auto immune 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 engineered 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 immunotherapy including gene and edited t-cells to treat these auto immune 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 are 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 in the lab don't come top down from me. They come from grad students and postdocs who have come filled with energy to bring their own ideas and progress is being made through this conversation of people in the lab reading paper is 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 I just looking backwards to 2013, 2014, we were struggling to see if we could get CRISPR into with electreparation 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 deliver a set of thousands of 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 and fruit flies but unimaginable and human cells were 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 of all opposed that we used to do these experiments race these cells against each other and see 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 telling us giving us a snapshot of what that cell is now able to do and we can also simultaneously measure which CRISPR was put into that cell and so now we can essentially inactivate every gene in the genome in t cells and

read out the consequences on the overall state of the cells and this is technology that was developed by a number of labs around the world. We've now deployed this at a massive scale to

directly in primary human immune cells. We just released 22 million cells where each one has a

doing in t cells but what other labs are doing around the world using CRISPR to read out the

“consequence of every gene in different cell types and different conditions as a sequel to the genome”

project. We talked about the genome giving us this draft of the DNA sequence. Now we can actually read out the function of every gene and see how each gene contributes to the behavior of every cell and this is being used with 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. 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 and immune cell to do? What do we want to recognize? Where do we want it to go? And we'll have a cheat cheat. It 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. Amazing. I mean, truly amazing. Should I be banking t cells?”

Well, I think the good news is that I never know what the answer is. This, I was going to say

the good news is that we largely have t cells. 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 to police 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, reendell them with powers. I would be disappointed if in the future

we would need to go back and take bank 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. I would only do it if you tell me too.”

A colleague of yours, Yamanaka. Yeah, I want to know about promise for essentially showing that you can take a skin cell, put in a dish, give it Yamanaka factors and work for 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 organ, I can always swimming

them 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 a bunch of these pluripotent cubriman in my case, Marson in your case, obviously, cells that if, you know, God forbid, I needed a bunch of pancreatic I let cells boom, they could have those within a week. This field is something that's been amazing to watch. It's, 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. So I was thinking, you know, you want to even draw blood, exactly, which would negate the need for banking. They if you had a year. So I don't know if, again, it's probably not something that I was be cost-effective for everyone to have there. Their IPS cells are ready to go.

I understand from, in conversation, from, from, from, with Shinya 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 broad sets of different people. So that could essentially be used as a transplant bank, which would 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 any patient when they're needed. So, but I mean, again, like, there's these different threads of things that being able to make endless supplies of any cell to wreck 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

still come from UCSF at the University of California San Francisco, but my lab's a 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 Shiniya Yamanaka, who maintains a lab at Gladstone in Jennifer Doudna, who also maintains a lab at Gladstone. Yeah, had to say yes. They're very clever. You had some psychologists for that. They

“got your number, so to speak. I described this, and I think that's not just a cliche. I actually”

remember kind of like that feeling of hair sticking off of the back of your head of like, oh, all of the 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 immune system, 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.

I have 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?”

Like it's so exciting that the tools are, they're here. And mostly I want to say thank you. Thank you for coming here today and giving us a absolute master class 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 is incredibly clear. I know people learned a ton. I know I learned a ton 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 our 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. I'd be honored. 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 not out of to be here. Well, thank you. It's a labor of love and I've loved this. So come back again. Thanks. 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.

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“Morrison. And last, but certainly not least, thank you for your interest in science.”

But you don't share it.

Egal, it's a very useful question. Do you do it with this story? And if you then

“know, it's a chain. - That's right. - Save. This story.”

Hold it, thanks for your time. Now, let's go out.