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

We're living in this amazing moment of biology where we can put a gene that encodes something on the surface of tea cells that will make them programmed to

search and destroy for cancer cells.

>> Now this is largely known as CART tea cells, chimeriic antigen receptor. This

is a receptor that was designed in a lab does not exist in nature. When those tea cells get reinfused into a patient the way that you get like a a blood transfusion, those cars are directed to

go against cancers. Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life.

I'm Andrew Huberman and I'm a professor of neurobiology and opthalmology at Stamford School of Medicine. My guest

today is Dr. Alex Marson. Dr. Alex

Marson is a medical doctor and scientist at the University of California, San Francisco. He is developing new ways to

Francisco. He is developing new ways to reprogram the immune system to cure cancers. Today we discuss how your

cancers. Today we discuss how your immune system works, how autoimmunity works, and how gene editing and other new technologies can be successfully leveraged to defeat childhood and adult

cancers. Dr. Dr. Marson is truly one of

cancers. Dr. Dr. Marson is truly one of a kind in his understanding of the clinical aspects of cancer treatment, the science of the immune system, and as you'll soon hear, in explaining the things that genuinely increase your

cancer risk, many of which are surprising, and the actionable steps that we can all take to reduce our probability of getting cancer. In

addition to the usual factors, smoking, UV light, and environmental toxins such as pesticides, we discuss the actual cancer risks that come from things like eating charred meats, airport scanners,

and food additives, and how to gauge your individual level of risk. We also

explore gene editing for reversing diseases, which until recently was science fiction, but now is a reality.

By the end of today's episode, thanks to Dr. Marson, you'll have the most up-to-date understanding of the state-of-the-art science for cancer prevention and treatment. Knowledge that

is certain to impact you or a close friend or family member in your lifetime. Before we begin, I'd like to

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

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,

public. In keeping with that theme, today's episode does include sponsors.

And now for my discussion with Dr. Alex Marson. Dr. Alex Marson, welcome.

Marson. Dr. Alex Marson, welcome.

>> Andrew, >> this is the first time that we're going to have a serious discussion about the immune system, cancer, and gene editing technologies on this podcast. So, I'm

delighted that you're here. It's also

great to see you again.

>> Thank you for having me. Really, really

good to see you.

>> It's been a while. Let's start off with the big picture.

>> Uh, how are we doing? How's uh how's biology looking? How's medicine looking?

biology looking? How's medicine looking?

Are we uh are we on the fast track to much better things? Are we going to slog along for another 10 years before we have cures to the many concerns that people have about cancer, Alzheimer's,

and the rest? Or are you encouraged by what's happening right now?

>> I think maybe there's some some the general public doesn't quite know how excited biologists are about what's possible. And maybe we've overpromised.

possible. And maybe we've overpromised.

Maybe in the past we've said we're on the brink of curing disease and people haven't seen it. But something is materially different right now. And

there is a convergence of so many different ways of understanding biology but then not having that stop at understanding but to actually intervene

and at the root causes of disease. And

over the course of this conversation, I imagine we're going to talk about DNA sequencing, understanding cells, but going all the way to rewriting specific DNA sequences

inside of the cells of our immune system. Doing this not one at a time,

system. Doing this not one at a time, but testing every gene and understanding pieces of DNA throughout our entire genome to understand what controls our cells. and then being able to take that

cells. and then being able to take that information and actually do something about it to boost our immune system to go after cancer to balance it for

inflammation and autoimmunity. And that

doesn't just have to be sort of searching for a pill. All of a sudden, we can actually talk to our own cells and give them instructions in the language of DNA and the language of molecular biology. And in some

molecular biology. And in some instances, this is being done with crisper, but it's also being done with lipid nanop particles and vaccines. And

we're still inventing new ways of giving these instructions. But all of a sudden,

these instructions. But all of a sudden, medicine is programming the behavior of cells in a way that's much more directed than was ever conceivable before. Like there's

really a step function in what's imaginable and achievable in medicine.

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

>> Yes is the answer. All of those things >> I think we can do experiments at a different level of scale. we can

generate data and then we have the computational tools in including AI but we have computational sophistication to actually extract insights from massive

amounts of data and you know I think historically biology was we were it was an observational science if you especially if you wanted to study things in in humans there wasn't a way to

intervene now all of a sudden we're taking human cells we're putting taking them into the lab and making genetic changes is and reading out the consequences and directly being able to

observe the effect. And we have all the we have tools to do this with imaging.

We have the tools to do this with DNA sequencing. And we can take this all the

sequencing. And we can take this all the way into clinical trials and see what are the what are the consequences when we actually go after targeted DNA sequences and make our cells better at

treating disease.

>> Would you mind educating us about the immune system a bit? the adaptive and the innate immune system, some of the major cell types, because I think those are going to form the kind of building blocks of our discussions about cancer

and and other things today.

>> Our immune system permeates almost every aspect of our health and disease. It is

a system really in the sense of it it's involved in every part of our body that has evolved to protect us largely to protect us against infections, viruses,

bacteria fungus.

all sorts of foreign invasions and our immune system has developed a balance that is when it's working properly doesn't recognize the cells that are

supposed to be in the body but is finely tuned to recognize signs of things that shouldn't be in the body and to eliminate them. I mean at at its core

eliminate them. I mean at at its core that's that's the the basic job of the immune system >> to recognize us versus non us.

>> Exactly.

And you you talked about the innate versus the adaptive immune system.

Largely what we're talking about are white blood cells. We're we're talking about different types of white blood cells that are either inside of tissues or circulating in our bloodstream that

go around and play coordinated and specialized roles in sensing when something comes in that is not us that's foreign that shouldn't be there.

The innate immune system does it as is sort of thought of as the the first alarm system that something something's wrong. And with the innate immune

wrong. And with the innate immune system, which consists of cells like dendritic cells, macrofasages, these are cells that are going around

and they're looking for patterns of things that just generally aren't in human cells. some signs of damage, some

human cells. some signs of damage, some signs of things that are just that shouldn't be there in a in a generic way in a healthy human. When those first alarm systems get triggered, all of a

sudden these innate immune systems start releasing things. They change their

releasing things. They change their state and they send off an alarm to other cells in the immune system and then they often recruit in the second arm of the immune system that you

mentioned, the adaptive immune system.

We'll talk a lot about the adaptive immune system today. And the major players in the adaptive immune system are a group of white blood cells that

are collectively known as lymphosytes.

But we'll talk about B cells and T- cells in particular, which are major groups of of lymphosytes. We've been

focused heavily on T- cells. TE- cells

play a central role in coordinating the fine-tuning of the immune response. One

of the amazing things about the te- cells is that each te- cell naturally in our body. It's one of the few places

our body. It's one of the few places where each cell will actually have a different piece of DNA that's not inherited in in our germ line sequence.

Each tea cell will make its own receptor that is generated largely at random to go and sense something. And those

those sensors that get put on the surface of tea cells are there to engage. And if they're engaged, it's a

engage. And if they're engaged, it's a sign that something has has been recognized as foreign. And so we have this incredible diversity of of different T- cell receptors that are

have developed on our tea cells. Each

one will have a different unique receptor on its surface. Each cell will have a different receptor on its surface. And the the way to think about

surface. And the the way to think about these receptors is that they're sensors for they're when they're engaged, they send a signal to the T- cell that okay, we found something that that you've been

programmed to recognize and program is recognized as far and if it if the immune system is working properly.

>> And are the genes uh that these tea cells make as these receptors uh are those based on experience of the of the organism? Because you said that it

organism? Because you said that it doesn't come from the germ line, but we should clarify that the germ line is not about infectious germs in this context.

The germline DNA is from the sperm and egg that were your parents. It became

you. There's re combination of those genes. And then there's you all um each

genes. And then there's you all um each and all. Um and the tea cells are making

and all. Um and the tea cells are making genes that neither your parents necessarily expressed nor that you were expected to express except based on what exposure to particular pathogens. Like

why do they make certain receptors and not others?

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

>> So it's probabilistic.

>> It's probabilistic and that's what allows us to have cells that lying there in waiting for things that we've never encountered. If a a a bacteria might

encountered. If a a a bacteria might come into existence or a virus might come into existence that doesn't even exist now in nature, but we might have tea cells lying there waiting that could

be engaged by those proteins on the surface that viruses would introduce.

>> That's incredible. Would you mind mentioning the the role of the thymus?

These days I'm hearing more and more about we have a thymus and we lose a thymus. Would it be beneficial if we

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

is is actually the reason the tea cells are called te- cells is the T stands for thymus and the thymus is an organ that it does sort of shrink as we age but at

least in childhood it's it sort of lies by your heart >> and it is the place where tea cells go in a key place of their education. So

they they've have are making these sensors at largely at random and then in the thymus they get cold they get selected and they the ones that by

accident are generated that recognize something that is supposed to be in your body if if the T- cell engages a natural target in the thymus those cells will

die and so what emerges from the thymus should be and this is not perfect process but should be things that have are have emerged at random but then are selected to remove things that recognize

your own body targets.

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

>> Yeah, that's exactly right. There's

actually both a positive selection and a negative selection. That's exactly the

negative selection. That's exactly the right way to think. The cells get will only emerge from the thymus that if they have a a receptor on their surface that's there. So that's one positive

that's there. So that's one positive selection, but if it engages with a self target in the thymus, it gets negatively selected. So what comes out are tea

selected. So what comes out are tea cells that are there with sensors in place >> to recognize things that shouldn't be there.

>> Okay. So your thymus and your tea cells get educated in childhood. Yeah.

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

recognize. the antibodies come from the from the other type of lymphosy lymphosytes. So now now we can talk

lymphosytes. So now now we can talk about the B cells. B cells are this other type of lymphosy that work in coordination with T- cells and they're the antibbody producing cells. So they

actually have a similar process where they're generating different antibodies at random through a similar kind of recombination event. they have their own

recombination event. they have their own form of selection that they go through and then those antibodies can then be released into the bloodstream and and are the basis for protection against

infections after we get them. I'd like

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helixleep.com/huberman to get up to 27% off. What um underlies the sort of efficiency and functioning of the immune system? I I know I and

many people are thinking, okay, we hear like our immune system gets activated or our uh our immune system is impaired. Um

the one thing that I'm certain uh supports the immune system is great sleep, >> right? And we just know this. If we

>> right? And we just know this. If we

don't sleep well or enough, we get sick.

Is that because there's a a known impairment of the immune system?

>> I I wonder about this too. I mean, I agree. I've experienced that so many

agree. I've experienced that so many times of being run down and then being being feel experiencing that I'm susceptible to infection, but I I don't

actually know the basis of that. I mean,

it's kind of amazing how much we don't know about these determinants of of immune health largely because they're often variables that are left out of the the mouse studies that we're doing.

We're, you know, we're studying largely steady state uh immune responses in mice. And I I would say we don't haven't

mice. And I I would say we don't haven't done a full exploration yet of all the types of ways that general health impinges on the immune system. I had a

someone in my lab a postoc named Sager Bapat who came to my lab with an interest in in in metabolic health and wanted to study the effect of metabolic health on on tea

cells and this there's some subgrowing stuff on this but it's another like what what are the determinants of it >> he did an he did experiments in my lab

where he exposed >> some an allergen something that irritated the skin and caused an allergic type reaction ction in the skin

of mice. He did it in mice that were

of mice. He did it in mice that were eating a normal mouse diet versus a highfat diet that caused obesity.

And what we saw was that it was actually not just a qual a quantitative difference in the immune system, but actually a qualitative difference. The

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

variables of life and test them in in a mechanistic way to isolate individual variants. What was interesting there was

variants. What was interesting there was that the allergic reaction actually looked totally different in the obese mice and if we used surrogates that are for the types of drugs that are being

used now to treat severe allergy. So we

gave antibodies that block allergic responses. the normal lip diet mice

responses. the normal lip diet mice would respond favorably to these. It it

they didn't help the the mice that had the obese highfat diet respon response to inflammation and in some cases it actually maybe made it worse.

>> So so I think that there are these these systemic ways I mean clearly we know we our intuition tells us this strongly that systemic health can can feed into

our immune responses but I think it's still been underexplored in rigorous ways. I realize I'm asking very top

ways. I realize I'm asking very top contour type questions for which there probably aren't specific answers, but we all know people that um get sick all the

time. Um and we know people who never

time. Um and we know people who never seem to catch the bugs that everyone else seems to catch. Is there any understanding of what a more robust immune system is at the level? Is it

more tea cells? Is it um you know are the the B cells engaged more quickly so they can generate antibodies more quickly? What is it?

quickly? What is it?

>> These are great questions I I that I don't think have full full answers.

>> There are there's been a lot of work on genetic determinance and and there's extreme cases where people have a genetic gap in their immune system where they're really susceptible to something that healthy

people should not be susceptible to. And

you see that there are certain types of infections that either happen or happen with a different type of severity in people with genetic deficits in c in certain branches of their immune system. And and in some

cases you can pinpoint that we just talked about the innate immune response, the adaptive immune response. You can

see that certain genetic mutations that people inherit could influence one or multiple branches of that immune responses and the consequences that you that manifests itself with different types of infection. And I suspect that

there's some spectrum of that that we see the the really you can diagnose the really strong genetic consequences and then there might be a long tail of more subtle genetic that might be multi multigenic that we don't fully

understand and then I'm sure that there's other determinants of health that are just multiffactorial and so it's you know it also becomes this

interplay between the health and then what you get exposed to by by your environment.

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

and um careful subtle >> increasing exposure to peanuts essentially um protects them against peanut allergies. So, is it true that

peanut allergies. So, is it true that when we're young that exposure to pathogens um and different foods uh

gives us a more robust immune system? I

think that there's the what we're exposed to and what we develop tolerance for is is critically important during there's some windows of early life that I think are we're particularly

susceptible to becoming tolerant >> and I think if we don't get the proper exposure to certain things all of a sudden our our body can start to be hyper sensitive to them which manifests as allergies now there's this balancing

act I think the fear of allergies makes people more more hesitant to expose kids and I think you can it can get into these these dangerous zones of you don't want to expose kids who are going to

have a a dangerous allergic response but on the other hand critical early exposure is part of how tolerance is maintained and I I think peanut allergies there there is strong evidence

that exposure to peanuts can be beneficial in people who are not yet allergic >> what's going on with autoimmune conditions

>> is this that the the B cells and T- cells are at probabilistic level that tea cells developed um some reaction so to speak a binding to um cells that we

naturally make that they shouldn't have.

It's just like it happens.

>> I've always been intrigued by by the idea that when the immune system is really ramped up >> um people will experience autoimmune like symptoms. I had experienced that as a master's student. I I was working so

much >> and probably not eating enough and drinking so much caffeine back then that I got some kind of funky skin lesion things. I went to the doctor and like,

things. I went to the doctor and like, "Oh, you're starting to get some attack of the deeper layers of of your skin.

Um, you just need to work a little less." And sure enough, did that trick?

less." And sure enough, did that trick?

>> It did the trick, you know. But I I was just it made me so keenly aware of how um the immune system will for lack of a better word adapt to conditions and it

was trying to keep me healthy and it it overshot the mark basically.

>> I sort of walked you through at a first principle like how things are supposed to work. I told you okay there's this

to work. I told you okay there's this process of generating receptors on the surface of T- cells. Antibodies get

generated on B cells. They go through this positive selection and negative selection. That's a delicate balancing

selection. That's a delicate balancing act and it doesn't actually work that way in practice. In in practice, TE-C cells escape from the thymus that do recognize our own self antigens and

there's actually secondary mechanisms there to block that. But autoimmune

diseases emerge when those normal checks fail.

>> This and I think it's a consequence that the immune system has two major responsibilities. It has to be primed to

responsibilities. It has to be primed to protect us from infections which would be fatal and be strong and recognize this incredible diversity of potential foreign dangerous things that we might

experience. But it also has to not

experience. But it also has to not recognize our own cells. And it can miss the mark in both ways. And so autoimmune disease manifests in different tissues.

If if you if your immune system starts recognizing targets in your joints, it can cause rheumatoid arthritis. If it's

in the cells that produce insulin in the pancreas, it causes type 1 or childhood diabetes. Um, if it's the my mileinated

diabetes. Um, if it's the my mileinated cells in the brain, it's multiple sclerosis. So, this is autoimmunity and

sclerosis. So, this is autoimmunity and inflammation of different kinds cause their own pathology. So, we want to the immune system is always these sort of two sides of the coin. Making sure that

we're having strong responses to infection.

We'll talk about cancer where we want to also strengthen our responses. But for

autoimmunity inflammation allergies we want to make sure that like our goal therapeutically in with drugs is to make sure that we make the immune system under control

and ideally do it in a targeted way so that you don't have to turn off the whole immune system with blanket immunosuppression, but to do it in a way that just makes you tolerant or not reactive against the things that are

being inappropriately targeted by the immune system.

Two things that I'd love to understand about the immune system is uh how is it that um an immune response let's say to

a cold virus is systemic like like where is the sort of master uh uh controller is it or maybe it's a distributed system that says like okay we need to launch a

a bodywide response as opposed to a localized response. I can I can imagine

localized response. I can I can imagine like with a splinter, of course, you're going to get a localized response.

>> It's a little piece of wood or metal and so you're going to get the innate response and you're going to get some pus around it and it'll kind of localize the wound. But

the wound. But >> when it comes to an invasive virus like the cold virus, uh it overtakes us, right? The production of mucus, we got

right? The production of mucus, we got the headache, like the and I think it's the systemic effect that um that intrigues me so much. like where is the signal to to to launch a systemic versus

a localized response in the immune system? How does it determine that? You

system? How does it determine that? You

know, I think some of it depends on on what virus we're talking about, how systemically invasive the the different viruses can be, and some of it can be that the immune system has different

levels of, you know, it can have a local response, but the immune system, the cells that we talked about in the immune system, one of their jobs can actually be to secrete things into the

bloodstream, things that are essentially chemical signals that something is wrong. major ones are they're called

wrong. major ones are they're called cytoines and they can act locally but they can also have more distributed effects and some of the things that that that the cytoines can do can influence

what can cause the development of fever right so you you can have these sort of cascading effects of something being recognized at a particular site in the body then sending distributed signals to the blood that will make us feel sick

and you know in some cases there's again this balancing act of maybe a fever gives us some edge in fighting s some some types infection, but it also makes us feel lousy. And so the you know the

the immune system is is always walking that I think in sometimes the immune system immune system response to infections is too strong and a lot of the the negative consequence of what we

experience is the immune system going too far and having to come back as as the as the as an infection gets under control.

>> Thank you. One of the reasons I asked that is well I hate being sick.

Fortunately I don't get sick too often if I take good care which I think is like most people. I think about antibiotics for instance. Antibiotics

are amazing.

>> Yeah.

>> I've had a few things where I was like, "Ah, this thing's bothering me." And uh like I had this sinus infection a few years back and I was like, "Ah, this is definitely not a cold." And then they tell you it's not a sinus infection

unless I was like, "I have a feeling."

Now, I'm not a physician of course, but um it got really bad.

And I took antibiotics and within a day I was feeling substantially better.

That's great. Many people have such experiences with antibiotics. I realize

they can be overprescribed and you can end up with antibiotic resistant infections. That's a concern for sure.

infections. That's a concern for sure.

But what is the sort of inherent danger of using things like antibiotics the way I described like not in a in a life or

death situation to mitigate the duration or the intensity of some sort of infection because surely you're shortcircuiting your immune system's uh ability to eventually just fight that

thing off. Like is part of building a

thing off. Like is part of building a robust immune system across your lifespan, allowing your immune system to do the work and going through the misery of being really sick and infected?

>> I don't think so.

>> Great. Okay. Fantastic. Love that

answer. Love that answer.

>> I think you probably were exposed and had an immune response. Antibiotics when

they're used for bacterial infections that that are susceptible to them are a miracle. And you know, we live in this

miracle. And you know, we live in this amazing sliver of human history where we have antibiotics that can cure disease.

I mean, I think many of us have had bacterial infections of different kinds, cuts and wounds that would have been deadly in other generations. And we're

we're we're the beneficiaries of having antibiotics that work. We are at some risk that if we overuse them, that window of human history might come to an end if we don't continue to replenish

new antibiotics. But we gain more and

new antibiotics. But we gain more and more bacteria that are resistant to antibiotics.

>> Are people developing new antibiotics?

>> It's an underfunded area of medicine >> because I just hear a moxicil pen. I

have a friend over in the UK who's been having some some eye symptoms that >> um from what I'm learning, we're still learning is likely an infection uh in near the posterior chamber, which just

simply means his vision is potentially at risk. Systemic antibiotics are very

at risk. Systemic antibiotics are very likely going to save his vision. And so

people say, well, antibiotics are bad.

Like a hundred years ago, we probably would have just they would have just inucleated the eye, which is be blind, right? So it's I think they're a

right? So it's I think they're a spectacularly good tool, but it seems like there's just a kit of maybe what a a five to a dozen very commonly prescribed ones. Why aren't people

prescribed ones. Why aren't people developing better, newer, new generation antibiotics? Seems like it would be a if

antibiotics? Seems like it would be a if for no other reason, a trillion dollar industry, but also save a lot of lives.

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

>> All right. Well, some entrepreneurial young uh guy or gal or both will will launch into it.

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

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. um that

cancer did not exist in uh our notsodistant past. I mean you hear this

notsodistant past. I mean you hear this like people say oh you know cancer is a new thing because of the advent of you know all these devices with EMFs and radiation. That's certainly not what I

radiation. That's certainly not what I believe. Has cancer been around a very

believe. Has cancer been around a very very long time. Do we have evidence for that?

>> Yeah. Yeah. I mean if anyone's really interested I I would highly recommend this book the emperor of all maladies which is a which is really a biography

of cancer as a disease and talk about I mean the long history of going back as far as there's records of tumors of various kinds and and the misery

associated with that we have a very different understanding of of cancer right now right and I think cancer is one of the most sophisticated where we have one of the most sophisticated genetic understandings of disease

doesn't mean we can always do things about it but now we can understand mutations that accumulate in in cells and all of a sudden so the DNA inside of

a healthy cell is there programming so if you have a skin cell your DNA is programming your skin cell to be a a skin cell in cancer all of a sudden some

combination of mutations emerge in that cell that lose its normal regulation it the skin cell is no longer getting the proper signals from its DNA to stay in the

right place and it goes and switches into a mode where it's dividing out of control and the result is that those cells will then transform into cancer cells. They'll start dividing. They'll

cells. They'll start dividing. They'll

lose the normal architecture. The risk

is that they can disrupt things in the in the tissue where they are or that further mutations can accumulate and they can actually start spreading into distant sites in the body and that's

metastasis. When you when you're when a

metastasis. When you when you're when a cancer goes from one local site to another part of the body and as that happens it the those cancerous cells

it's it's really an evolutionary process where those cancerous cells have acquired new genetics that are focused on their well-being. Those cells are dividing. They're growing out of control

dividing. They're growing out of control and they're taking the resources.

They're they're they're growing at the expense of the normal coordination of the human body. And and that's that's really at at its core what what cancer

is. It's genetic disease where cells

is. It's genetic disease where cells lose the normal pro uh regulation and are dividing out of control in various tissues.

>> I can see the picture in my mind where a otherwise healthy cell gets a mutation.

We can talk about how mutations arise but and then starts uh spitting off daughter cells as it's referred to.

>> Yep. Why would the daughter cells inherit the mutation necessarily to then create more cells because that's the prol proliferation of the tumor?

>> Yeah, >> certainly cells propagate their DNA into their daughter cells. But um

I could imagine a situation where every day some of our cells get a mutation, spit off a couple daughter cells, and then those daughter cells are are terminal as we say, right? And they

don't create more cells. Is that

happening all over the body every day?

So does this so how is it that a the DNA that creates the further propagation gets passed from one one cell to the next? I do think this is happening

next? I do think this is happening constantly. It's a process that every

constantly. It's a process that every time a cell is around especially as it's dividing there is some imperfection in how the DNA the DNA has inside each of

our cells if that cell is going to replicate the DNA has to replicate itself. So you end up with two copies of

itself. So you end up with two copies of DNA that should be the same. Each one

being passed on to the two daughter cells of that dividing cell.

That process of DNA replication is imperfect. And if there's any kind of

imperfect. And if there's any kind of damage during that process, one of those two copies might end up different than the other one, in which case you end up with a mutation now in one daughter cell

and not the other.

If that is dilitterious or if it's damaging, which probably most mutations are, those cells might start to die off.

Okay. Something got the DNA got messed up. Those cells that are carrying that

up. Those cells that are carrying that DNA die.

>> Yeah. They can't take up glucose. They

can't they just can't do cell stuff.

>> And there's a lot of control mechanisms in the cell that say something something's wrong. Let's send a a

something's wrong. Let's send a a programmed cell death signal to that cell. And cells will kind of implode

cell. And cells will kind of implode with with various processes when something's wrong. And that that happens

something's wrong. And that that happens most of the time. The problem is if if if that change all of a sudden starts to not be damaging but to actually be a

signal. Okay, now the cell is is growing

signal. Okay, now the cell is is growing more. It has some benefit that it's

more. It has some benefit that it's accumulated as a result of that mutation. Now that cell will start to

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

more. It both of its daughters now will pass on this this mutation that's made it divide more. And if in subsequent rounds it gets a second hit, it that the

combination may go from just cells that are dividing a little bit more to cells that take off and become full-blown cancer. Now, there's certain processes

cancer. Now, there's certain processes that will accelerate that.

>> One was exposure to things that cause DNA damage, right? The major one is is smoking. When smoking causes chemicals

smoking. When smoking causes chemicals to go into your lungs, the the lung cells get exposed to these chemicals that then cause higher amounts of DNA

damage, more mutations, and just as you have more mutations at a higher frequency, you're more likely to accumulate the set a set of mutations that will gradually go on to cause the

generation of cancer. Another way that is that this process can be accelerated is that some people carry an underlying genetic predisposition to cancer. So

people you will likely have heard of the brocha or the BRCA genes which predispose to breast cancer and other types of cancer. There people start with

one copy that's already setting them on a road to higher risk of mutations accumulating and the whole process on in

happens with a higher frequency and so this this march towards cancer cells is more likely to occur in people with that type of predisposition. How common is

the BA mutation? Uh is it equally distributed in men and women? Um yeah,

what can you tell us? And should

everyone get tested for BA? And there's

a lot of questions here. I'll ask them again one by one. Um and then of course we'll talk about things that could be protective, not just but certainly avoiding smoking would be paramount. So

how common is >> breath? Yeah. So in terms of mut

>> breath? Yeah. So in terms of mut mutagens like the big ones are smoking >> sun exposure for melanoma. You know I know the balancing features of sun exposure but >> yeah we can talk about that

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

>> I mean I'm perfectly happy going on record. My the things I've said around

record. My the things I've said around in sunlight have been contorted so many different ways. It's like a pretzel

different ways. It's like a pretzel twist now. No it's more like one of

twist now. No it's more like one of those balloon animals at a party but it's not it's a mess. The too much UV is bad for for skin cells. It's just bad.

You need some, but too much is bad. Long

wavelength light is great uh for and therein lies the challenge. But yeah,

love sunlight, but you don't want excessive UV. Don't get avoid getting

excessive UV. Don't get avoid getting sunburned, folks. Yeah, thank you.

sunburned, folks. Yeah, thank you.

>> So, yeah, the BA mutation. And I have a personal relationship to this cuz I lost both my graduate adviser and my post-docctoral adviser to bracka mutation related cancers 50 and you know

just a little bit older than 60 and the other and you know brutal um especially when you you know one of them I know they're kids and you know it's um just for young people getting cancer and I

know they're childhood cancers but ba seems pretty common.

>> I don't know the numbers off the top of my head. I mean they're not the major

my head. I mean they're not the major like numerical causes of of of cancer in the scheme of cancers that developed.

It's it's it's a it's a minority. It's a

relatively small set number of the full set of cancers. The problem is if you inherit a broco mutation as an individual you have a very high risk of developing cancer. So it as an

developing cancer. So it as an individual your risk goes way way up and of certain types of cancer in particular >> and we can all get tested for it now pretty cheaply right.

>> Yes.

>> Yeah.

>> Yeah. That's certainly recommended if there's a family history of of cancer for broa mutations and a a couple of other ones. But you're right it's the

other ones. But you're right it's the tests are available. And you asked about men and women. Mhm.

>> It actually was was men were were some of the ways that those broco genes were identified because it's so rare for men to develop breast cancer. The ones who did develop it there was a thought well

maybe there's an underlying genetic predisposition and that helped identify those genes.

>> Interesting. Um everyone get tested for broa if you know because there are lifestyle factors that can reduce your cancer risk. I'd like to talk about

cancer risk. I'd like to talk about mutagens. Yeah. Um, smoking bad. I'll go

mutagens. Yeah. Um, smoking bad. I'll go

on record saying vaping bad. Perhaps not

as bad as smoking, but still way way worse than not vaping. Uh, the battle to sort of protect vaping is is like beyond me. But, um, okay. Uh, to each their

me. But, um, okay. Uh, to each their own. Um,

own. Um, environmental sort of and workplace hazards, you know, like known mutagens.

If you work in a laboratory, you're working with mutagens, right? You're

working with things that literally pull DNA apart. Yes. This always worried me

DNA apart. Yes. This always worried me working in a laboratory. There are a lot of carcinogenic chemicals in a laboratory >> for good reason. Yeah. This is the Yeah, we're we're trying to study cancer, but we're certainly working around a lot of

things that could cause cancer, chemicals, >> radiation.

>> Uh yeah, I don't know if you about you.

I did a lot of lot of experiments radio lababeling cells.

>> Yeah. I mean we well fortunately we worked with uh you know radiotagged amino acids with radiation that was we were told and I do believe was not not as as dangerous as

some of the others but yeah I mean so chemical exposures are a big one. Yep.

>> And so those those labels on paints and thinners and stuff in the garage that's real that's a real thing. They mutate

cells >> and there's a you know there's some spectrum of stronger and less strong ones. And I think oftenimes we're

ones. And I think oftenimes we're operating in an absence of great data, but I you know I think there's a lot of things are implicated as potential mutagens, >> pesticides. Yeah, I

>> pesticides. Yeah, I >> you look at cancer rates in in um rural areas near where you know crops are dusted with pesticides and we've had Shauna Swan came on here and she's like

listen you know the the cancer risks the you know endocrine disruptor risks we think of as like big cities as as dirty and dangerous and they are for certain reasons but she said if you really see

the spikes in uh in these cancers uh related to environmental factors it's less so bus exhaust than it is pesticides.

>> I mean, it is not evenly or fairly distributed. Some people get exposed way

distributed. Some people get exposed way more to these things and we haven't studied them enough. We we need way more study to really be able to answer. Okay.

And and and people shouldn't be left, this is my just me just speaking as it's kind of amazing to me how much we're left on our own to be figuring out what the risk of individual products is. And

I I think it's a place where we should be investing a lot more to get clarity on where the real risks are.

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

X-rays cause mutations.

>> Yeah. Again, there's a tradeoff and the dose and I, you know, when you need an X-ray, you need an X-ray, but I wouldn't do them for fun,

>> right? Um I mean I have colleagues who

>> right? Um I mean I have colleagues who prefer to do the slower um manual pat down at the airport um to going through the scanner. It's a low level of

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,

low-level exposures. And we know pilots, and this is for other reasons because they're, you know, you can tell us, but atmospherically they're exposed to more radiation. Cancer rates are higher in

radiation. Cancer rates are higher in pilots. Now they're sitting a lot too.

pilots. Now they're sitting a lot too.

Prostate kids. Okay. There's a bunch of things there, but um do you yourself avoid the scanner at the airport?

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

>> bias of less seems better.

>> Yeah. I mean, I'm not out to get the the scanner industry. Yeah, just I think

scanner industry. Yeah, just I think it's useful for people to hear that that you could that one can have no formal data but an understanding of mechanism that leads them to >> to hedge.

>> Yeah, >> it's good to know. Are there any um mutagens and >> well is a carcinogen and a mutagen the same thing?

>> So they're they're closely related.

Mutagen I think means that you're mutating that you're changing the DNA in the cell. That's that's the idea that

the cell. That's that's the idea that it's those mutations may or may not be linked to to cancer, but by virtue of the fact that you're causing more mutations, almost inevitably you're also increasing the risk of cancer and

carcinogens are things that increase the ris rate of cancer.

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

>> Yeah. Yeah.

>> Is the char bad?

>> I think so. I mean, I like it, too, but Yeah. Yeah. Again, these are balancing

Yeah. Yeah. Again, these are balancing decisions in life. Sure. But yes, there there there's some there is I mean meat in general has been implicated as a potential carcinogen, especially in colorectile cancer. There's some data

colorectile cancer. There's some data around that.

>> Mhm. Yeah. My read of those data, not the char data, but the the me data is it's tricky. Um

it's tricky. Um >> from my this is just my standpoint. And

I want to make sure I'm I put you know brackets around this that this is my read of the literature is that many of the studies that looked at >> meat rich red meat rich diets versus uh

plant-based diets. The problem is a lot

plant-based diets. The problem is a lot times the red meatenrich diets had a bunch of other things in them like sourcing wasn't considered. There was

also a lot of um starches like because nowadays you find people who seem to at least feel better. Who knows about the longevity aspect, but feel better eating red meat, fruits, and vegetables,

limited amounts of starches versus so I feel like the nutrition studies are a mess. They're kind of a disaster.

mess. They're kind of a disaster.

>> I I certainly don't have clarity on that. Yeah. Yeah. And they and it seems

that. Yeah. Yeah. And they and it seems like it changes the the the direction. I

think some things we have pretty good common sense intuition about >> fiber.

>> Yeah. ultrarocessed foods are probably bad like you know but I I think the balance of exactly what whole foods we're eating probably still needs to be worked out.

>> How do you think about the data um on like for instance food dyes this is very timely um where a certain food dye yeah >> at a very very very high concentration

in laboratory animals creates a significantly higher >> incidence of of tumors and cancers in those animals. But then the amount of

those animals. But then the amount of food dye that's in the human food is is is a tiny fraction of that. Um I'm not trying to get political here. I just

think as a framework for people to think about >> there are many carcinogens I'm sure right in this environment. I don't doubt that the lacquer on this table in fact if that's even what they used um uh if

ingested could cause um could cause cancer. I don't I don't doubt that.

cancer. I don't I don't doubt that.

Right. But I don't know that in its in its form here being near it uh for many hours a day does that. I I doubt it.

We're not inhaling the table.

>> This is what I mean by this this this level of confusion. I think we all live with this background confusion of things some study has been published in in mice at whole high concentrations exposure

does mean anything in our lives. What's

the relative risk? So that's why I start with smoking sunlight and then say there's a tail. And I I don't think we know fully what that distribution is yet. I'm sure there are some combination

yet. I'm sure there are some combination of things that are increasing our risk of cancer. We don't really know how to

of cancer. We don't really know how to weigh uh duration and amount of exposure. And this is why I think it's

exposure. And this is why I think it's really scary to people. People don't

know, you know, they know smokers who don't get lung cancer >> and non-smokers who do >> and non-smokers who do. And so I think people go well like what they it actually has caused I I believe a lot of

um damage in the faith in in medicine unfortunately because the messaging is all uh is mixed up.

>> Yeah. I think that nowadays people are trying to do what they can to protect themselves, but people still get cancer.

You can do everything right and still get cancer. Is that

get cancer. Is that >> even if you don't have a bracket mutation?

>> Absolutely. I mean, absolutely. You

know, I think the last thing you ever want to do is like attribute someone's actions to to cancer. I mean, it is it is a probabilistic disease where some

set of mutations occur that cause a really devastating disease. And so I yeah I mean I we don't know the answers and I think we have to be humble about that. Now what I I think we can also

that. Now what I I think we can also talk about is well like how how do we handle how do we treat cancer when it comes up and this is where these two conversations that we've been having really come together of when talking

about the immune system. We went through a lot of I think I mean actually we went through a lot of sort of detailed mechanism thinking about the different cell constituents of our immune system.

I will tell you that when I went to medical school, which wasn't that long ago, I graduated in 2010, the dogma was don't waste time thinking

about cancer immunology.

Cancer immunology is a field that's going nowhere.

>> I mean, I think I I I was in Boston. I

think that was a maybe there was some local bias in that direction, but this was not the mainstream of thinking about how we would treat cancer >> at that point. that the way the cancer was being treated was chemotherapy,

which you know is something that's been around for decades. And it's basically give toxins to the body that will be more toxic to the cancer cells than to the healthy cells. And ask people to

endure all the side effects because they have to to get rid of the cancer cells.

And that's still the mainstay of of of cancer treatment. We all want to do

cancer treatment. We all want to do better than that.

>> It's very unpleasant. Very very

unpleasant.

>> Unpleasant and and worse. I mean I mean people endure hor you know it's it's we put put we put people through horrific things because it's the best we can do >> and then there was a wave of thinking

okay well let's try to make drugs that are targeted to the mutations that we talked about and that was that was the hot thing that was the promising avenue when I was in medical school of like okay now we we've really measured that

these are mutations that accumulate inside of cancer cells this is what's causing cancer let's let's make drugs that go after those things And turned out that that was although a lot of good

has come from that people have extended lives, cancer has a way of working around that. And

around that. And >> so these are cell cycle inhibitors.

>> So signaling thing various mutations affect this these growth properties of of cells and there's targeted drugs that have been designed to go after some of those pathways that are making the cells

divide out of control. Yeah, I think that benefit has come but cancer has ways of mutating around that and become developing resistance. The same way we

developing resistance. The same way we talked about resistance in bacteria to antibiotics if they're exposed you can cancer cells are can evolve quickly and can become resistant to these targeted

modifications.

What has emerged as a whole new way of thinking about going after cancer is using the power of the immune system that we talked about at the beginning and redirecting that against cancer

targets.

This has changed how we think about cancer treatment. It's the hope is that

cancer treatment. It's the hope is that all of we tal we we talked all of us have this immune system that goes through every organ in our body. It

circulates. We have white blood cells that are constantly going around and looking for things that shouldn't be there.

Can we unleash that immune system against cancer?

And the hope would be that the cells that our immune system, we've talked about how they're really exquisitly evolved to make a determination of this is a healthy cell, this is not a healthy cell, this this cell should be here, this should not.

>> If we could get that level of precision where we could have a durable immune response that gets rid of the cancer cells but leaves the healthy cells intact, that is what we want. Mhm.

>> Now that is not science fiction and has is is now approved and used to treat a number of different cancers. The first

place where this happened was in a class of medicines called checkpoint inhibitors.

>> Um or amunotherapy drugs uh a lot of a lot of people will have heard of these things. PD1, CTLA4 are some targets

things. PD1, CTLA4 are some targets where there are drugs that get infused that hit these things that are on the surface of TE-C cells and they actually

are natural breaks to the TE- cells.

Te-E cells might be in our body there but turned off or not turned on enough to be strong enough against cancer. And

for certain types of cancer, it's been absolutely miraculous that if you make a drug that hits the break on the on the tea cells, the tea cells go stronger and they can be unleashed against cancer

just by taking the brakes off of them.

>> What sorts of cancers has it been successful for?

>> The poster child for this has been melanoma. Mhm.

melanoma. Mhm.

>> One of the big success cases was was Jimmy Carter who had a melanoma which is a skin cell aggressive skin cancer that had already gone to his brain which was thought of as a death sentence and he

got treated with checkpoint inhibitors and basically was cured.

>> Amazing.

>> Um and so you know they saw these tumors just shrink away and in and not just him but in a in a large fraction of of melanoma patients now respond to these.

And so that that has changed how melanoma is treated. It's and other cancers to varying degrees because some types of cancers can respond to this.

That's taking the a drug that unleashes the tea cells that are already in our body. The focus of my research in is

body. The focus of my research in is well the first thing I said was we're living in this amazing moment of biology where we can we can do things to cells in our

body that with incredible precision and and we're often just limited by our imagination. And what we can see now is

imagination. And what we can see now is that we don't actually have to just be limited to the cells that the tea cells that are natural in our body that already have this random distribution of

sensors. We can actually genetically

sensors. We can actually genetically make a a one of these sensors for tea cells and put it into te- cells. We can

put in put a gene that encodes something on the surface of tea cells that will make them programmed to search and destroy for cancer cells.

>> Now, this is this is largely known as chimeriic antigen receptor tea cells.

That's a long term. They're known for short as CART cells, chimeriic antigen receptor. And what that means chimeic is

receptor. And what that means chimeic is that these are stitched together. This

is a receptor that was designed in a lab, does not exist in nature, but can be put into a piece of DNA, delivered into a TE-C cell, and when that DNA goes

into the genetic code of the T- cell, all of a sudden the T- cell will start making proteins that go on its surface and act as these artificial sensors. And

those cars then when those tea cells get reinfused into a patient the way that you get like a a blood transfusion those cars are directed to go against cancers. This has been done for certain

cancers. This has been done for certain types of leukemia and lymphoma. And

there's been these amazing success stories. The thing that woke up me and

stories. The thing that woke up me and the world was in 2012 there was a young girl who was the first pediatric patient to be treated with a

cartis cell for for cancer. So she she's become a heroic figure uh Emily Whitehead. She was I think eight at the

Whitehead. She was I think eight at the time and she had a form of leukemia that hadn't resp it just was for some reason whatever reason it failed all the

treatments and it just nothing worked.

She was going to be sent home on hospice. She had exhausted all the

hospice. She had exhausted all the possibilities at the age of eight and she got enrolled in a at that time highly experimental treatment to get these CAT tea cells. So her blood cells

were taken out in a big blood donation.

her own tea cells were genetically modified and we could talk about how that was done. It's actually done with like a pretty crude technique that's been around actually used viruses,

lentiviruses. These are sort of modified

lentiviruses. These are sort of modified HIV viruses to deliver this extra piece of DNA that encoded the car. And this

was done on her cells. And then after that extra gene was put into the tea cells, the tea cells were reinfused into her body. And it was not a

her body. And it was not a straightforward course. She she ended up

straightforward course. She she ended up in the ICU. The immune system had to we people in real time people had to figure out how to control the immune systems and the side effects. But as that was controlled, all of a sudden the her

cancer cells disappeared.

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

>> No, amazingly it really hasn't. I mean

there there's been some discussion about the risks of using these lentiviruses and we we'll talk in a second about how we can do better now.

>> Yeah. People are going to hear uh putting viruses into cells and putting them into humans and a bunch of people will freak out. But I I promise you that things like adeno, which is like a cold virus, or lenti, which is similar to

HIV. And of course, they didn't give her

HIV. And of course, they didn't give her HIV. They changed the virus, so they're

HIV. They changed the virus, so they're not delivering HIV. These viruses are incredible because they can create longlasting expression of genes that you deliberately put into them. They're a

shuttle.

>> It's an amazing application of biological understanding, right? that

all of a sudden we've been studying viruses because of the risk that they have, but we've learned that they can deliver that that viruses have evolved to be very good shuttles >> and to deliver their genetic material

into cells.

>> The way I think of it uh that is the viruses have evolved to take advantage of our biology and our genes. And so we did the ultimate touch in these

instances like you're so good at at hijacking our cell's DNA and proliferating. All right, we'll leverage

proliferating. All right, we'll leverage you to help us as opposed to hurt us.

Right.

>> That's exactly right.

>> And so that was done in 2012. Emily

Whitehead was eight.

It was done as an experimental treatment at the University of Pennsylvania. And

the story now is that now all these years later, Emily White is not only cured of her leukemia, she's premed at the University of Pennsylvania.

>> So awesome.

>> And so no one could ignore that. You

know, this was this wasn't this was just all of a sudden this dogma that I had just been taught a couple of years early in medical school that we should ignore cancer amunotherapy. It was just we were

cancer amunotherapy. It was just we were just wrong.

>> And all of a sudden the field woke up and said, "Okay, the immune system is not just limited to treating viruses and bacting us from viruses and bacteria.

The immune system can be exploited and potentially re-engineered to protect us from cancer and maybe other diseases."

So that was 2012.

2012 also was the year that a paper got published in science by Emanuel Sharpantier and Jennifer Dana that introduced this new technology called crisper

and we can we'll talk about this but crisper fundamentally is a tool to rewrite DNA sequences that came out in 2012

and on a personal level 2012 was also the year that I moved to San Francisco to start a lab studying tea cells and how genetics influences te- cells. I was

looking around and trying to figure out what my lab would do and all of a sudden I was arriving with a empty lab space at exactly the same moment that that the world was shown that te- cells could

cure cancer and that we had a tool that could potentially rewrite DNA sequences and that we wouldn't be limited to these lentiviruses which are kind of clunky the best tools we had at the time but pretty clunky and non-precise in how

they insert genetic material. All of a sudden, we could imagine that we could take tea cells and use crisper to actually pick individual places in the genome and make targeted changes to

program exactly how cells behave. And

that is the basis for my ongoing work.

We've put a lot of work over the years into being able to now take crisper technology, get it to work in TE-C cells to learn the rules about what are the

genetic changes that will be most effective at making TE- cells into into amunotherapies that cure patients for with different diseases and then to

go all the way and then actually use crisper to make tea cells that can be input into patients with new levels of precision and power and that's that's in

clinical trials now. We're now in clinical trials with these crisper engineered CARTT cells and we're not just going after leukemias where these

CARTT cells have historically worked but we're also thinking about can we make these work for the really common causes of cancer deaths solid tumors and that's

been a challenge and we can talk about that but getting tea cells to find the right targets in tumors and then work inside of tumor environments which are inherently imunosuppressive

requires figuring out additional gene edits that are now possible with crisper to try to beat the cancer at its own game. If cancer is evolving to to make

game. If cancer is evolving to to make itself cloaked from the immune system, now with crisper, we can think about getting one step ahead and making tea cells that are able to be resist all the

tricks that cancers throw at it to be more and the I think we're on the brink of having precise crisper engineered cells that will I I hope start to melt

away cancers without the side effects of chemotherapy.

>> Amazing. Uh just amazing. And the story of this young woman is spectacular. Um,

>> I have two questions before we talk about crisper technology. The first one is, is it true, I believe it is, but is it true that cancer risk goes up as we get older?

>> And if so, why? Um,

so that's the first question. And then

uh the other question has to do with how the the amunotherapy that you described um was able to target the cancer and and not cause problems elsewhere which is kind of the major issue of chemo and

radiation therapy. But the first

radiation therapy. But the first question um again was you know why more um mutations as we get older. So I think there's there's a few cancers that that peak in childhood and there's risk as as

the body's developing of certain cancer childhood cancers and there's childhood leukemas for example then that like when we talk about Emily Whitehead but most cancers as you said exactly as you said

that there's this sort of increase and they're largely disease of later stages of life. I think that the reason for

of life. I think that the reason for that is remember when we talked about what causes cancer it's this evolution where c cells start to accumulate mutations numerically a lot of the cells

that have the mutations will die off and it's just a game that unfolds over time and the more time you have cells dividing and sticking around in the body they're accumulating more damage and eventually you're more likely that that

damage would actually transform the cells into a cancer cell. So time is is is is a big factor here. time and just accumulated damage.

>> And the other question was, you know, how is it that the lentivirus knows to um the lentiviral

uh cargo carrying tea cells uh know to attack the cancer and not something else.

>> So this is a key question for the field, right?

And I think one of the things that worked incredibly well was a brilliant choice by a group of scientists in different a few different places that converged on the target that was used in

the first CARTT cell. And what the target is known as as is is a protein called CD19.

>> That's just the name of this thing that's found on a lot of different types of B cells. So this brings us back to this discussion. the the leukemas

this discussion. the the leukemas themselves are a disease, a cancer of the immune cells. So they're cancer of B cells and CD19 is is found on the on the

surface of many a large number of different types of B cell leukemas and lymphas.

>> I see.

>> I think one of the things that turns out to be serendipitous here is that B cells themselves natural healthy B cells actually also have CD19 on their surface. What just turns out to be

surface. What just turns out to be serendipitous is that the body can tolerate those cells going away. And so

what has made this a particularly effective and safe and relatively well tolerated treatment for cancer is that the collateral damage is actually not that damaging. That te- cells in this

that damaging. That te- cells in this case are not strictly distinguishing between cancer and health. They're not

just getting the leukemia cells. They're

they are getting collateral B cells. But

by and large to a first approximation, people can live without those cells. And

so that side effect has just been tolerable.

Finding that balance gets harder and harder for more cancers. Right? If you

start to think about pancreatic cancer or brain cancer, finding targets that if you hit the healthy pancreas or the healthy brain are not toxic, it's it's

harder and harder. So people are thinking about more and more sophisticated ways to look for these targets that are selectively found on the cancer cell and not on the healthy cell or to think about ways that you

might actually make the cell depend on recognizing multiple features so that you can have what's sometimes talked about as like a two-factor authentication like the T- cell will

only kill cancer if it finds this and this and that combination of things are not found on healthy cells even if one or the other might be. So people are thinking about how do we

>> get more sophisticated about building these discrimination systems into tea cells. The building blocks are there but

cells. The building blocks are there but the specifics for each cancer have to be invented but but we have the tools to do that.

>> Awesome. Before we talk about crisper there was one other question that I know many people will be thinking about. Uh a

few years back, maybe five, ten years back, there was a a lot of discussion, maybe even some enthusiasm about ketogenic diets to treat or prevent

cancer. And my understanding from

cancer. And my understanding from looking at that literature was that for some cancers it perhaps, I want to bold uh underline and and capitalize perhaps

um might help, but for other cancers it could make things worse. And then uh I also more recently started hearing about uh low glutamine diets. Um so and of

course this is the way the internet works but um but I did see some papers in some decent journals you know uh that at least we're exploring this. So are um

low they're just low carb let's call it what they are ketogenic diets um have they been shown to be useful for treatment or avoidance of cancer?

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

Yeah.

>> Okay. My my guess is that um people are still looking at this, but you know there was also the idea that they could be useful for um certain forms of dementia. There was an effort to call

dementia. There was an effort to call dementia, you know, type three diabetes, but my understanding from talking to the experts in this is that um it might help through indirect mechanisms, but that

it's not going to solve the problem. Um

okay. Well, thanks for entertaining that little uh culde-sac that I created.

>> Crisper, tell us the story of Crisper.

Uh because I think crisper is one of those funny things in biology and medicine that almost everybody has heard about in the general population. Most

people know it has something to do with changing genes, but it's sort of like AI.

>> Yeah, >> it's here. Uh it's powerful. It scares

certain people. It excites other people.

Um but most people don't know how it works because there's really no incentive to. But I think the story of

incentive to. But I think the story of Crisper is actually also a story about uh how science works >> and that's important too.

>> I think it's exactly true. I think it is a perfect illustration of something where a discovery happened that no one was planning

>> but changed biology. Um

let me tell this story in two separate arcs. One arc is the arc of

arcs. One arc is the arc of understanding DNA. You know, if you go

understanding DNA. You know, if you go back to Watson and Crick, it's understanding the double helix to understand the structure of the DN what a DNA sequence is that mature as we

learn how to sequence to understand the to be able to measure a row of ATS and C's and G's that in whatever combination they are will start to be the building

blocks for programming which proteins get made inside a cell. And then around 2000, we get to the first draft of the human genome, which is this multi-billion dollar project across the

world to come up with a draft of one human genome sequence milestone for for biology and medicine.

And then DNA sequencing technologies continue to improve and cost comes down.

We're getting to the point where we can start to measure big chunks of our DNA at increasingly affordable costs. And

people were starting to understand the differences between people with DNA at the level of at least statistics. Okay,

people with this disease are more likely to have this this gene than that. But

we're getting to some limit of what we can do just by sequencing DNA. All of a sudden, you you're observing the DNA sequence that's in someone's cells, but you don't really know what those effects

are. Just as the sequencing world is is

are. Just as the sequencing world is is maturing, we're desperately looking for a tool to say, well, now we want to as we have all the sequences, we want to be able to see

what happens if you change a sequence.

And people were stumbling around looking for different tools. There were there were

different tools. There were there were there was a range of these things. There

were zinc fingers. that people

lentivirus was another one that we just talked about that with different degrees of efficiency and people were trying to to be able to change DNA sequences and cells and it had been a long-standing

effort.

Out of nowhere emerges crisper as the answer to this problem. crisper was

being studied as an an interesting and unusual set of DNA sequences that were found in certain types of bacteria.

There were these repeated sequences and no one knew what they were. And people

out of real basic curiosity about what was happening in bacteria started studying these repeat sequences and what they were doing. And little by little by little it was worked out that these

repeat repeat sequences actually ba formed the basis of a kind of immune system for bacteria.

>> Now we talked about the human immune system. Bacteria are just an individual

system. Bacteria are just an individual cell but they're also susceptible to infections which is a sort of a strange idea. Bacteria cause infections in us

idea. Bacteria cause infections in us but there's this arms race between organisms. >> Everyone's trying to kill everyone else.

>> And so bacteria are constantly being bombarded by certain types of viruses.

They're called bacteria phagee viruses and they've evolved a series of bacteria have evolved a series of defense mechanisms to protect themselves from

from these viruses. Crisper turns out to be a bacterial defense mechanism against viruses which is kind of amazing that this that this thing that has entered into popular

culture is a bacteria protection against bacteria phage. Now why has this caught

bacteria phage. Now why has this caught the world of biology by storm? Well,

what was realized was that the way that that crisper works to protect against itself um the protect bacteria from viruses is

that it can recognize particular sequences of DNA which are virus sequences and discern discriminate whether it's a virus sequence or its own

bacteria sequence >> and it actually does that by scanning across the DNA and finding something that's recognized as a virus target and

not a bacteria target. And when it finds it, it makes a cut.

Okay, now this sounds technical obscure, but what was recognized and this became the basis for a Nobel Prize of of with Jennifer Dow and Emanuel Sharpentier.

Many people around the world have contributed to this field. Um what was realized was that this could be repurposed as a tool. If we take it out of

bacteria, we could actually exploit this with this crisper system that had evolved to protect bacteria. And the

same rules that allowed bacteria to to scan across DNA and find a virus sequence and cut it could be used to scan across any DNA and cut at a

particular sequence.

That's the power of crisper. Now, why do we care so much about being able to cut a particular sequence? If you can cut, you can also start pasting. You can cut out genes that are limiting the that you don't you don't want to be in a cell.

You can start pasting in sequences to replace mutations that cause disease. We

can start pasting in big sequences like the sequence for cars or other types of things that will make TE- cells more powerful. So, and this is I'm I'm

powerful. So, and this is I'm I'm focused on TE-C cells, but this is in now in every aspect of biology. People

are studying this in plants and to make crops that will be drought resistant.

People are studying this in in in every organ system to understand every type of disease and to build new new types of molecular medicines.

There's one other feature of crisper that's that's really important in this story. It's not just that this crisper

story. It's not just that this crisper can cut at a specific sequence that it's evolved to cut at virus sequence. It's

the way that it cuts that has made it really catch on in a way that none of these earlier technologies do. So

crisper, if you think of it as a it's an enzyme that can cut DNA and it it can cut essentially almost any sequence of DNA. So how does it decide

which sequence to cut? It does it by actually pairing with an RNA molecule.

So crisper sometimes called cast 9 which is a particular type of crisper system um is a is a combination of a protein which is

a scissor and then an RNA that sticks to it and the RNA is what actually programs where that scissor will cut. Okay. So

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

sequence. There's a complimentarity

sequence. There's a complimentarity where you you can match up and know exactly which RNA you want to design. So

you can now cut DNA sequences at will.

And it's gotten to the point where now if we want to cut a piece of DNA, we order a piece of RNA off the internet.

It shows up in in in the lab in a matter of days. We mix it with cast 9 protein

of days. We mix it with cast 9 protein and then that's going in tea cells the next day and we're able to introduce a cut into any DNA sequence. So now you go

back to the genome sequence that was came out in 2010 and all of a sudden you can go on the internet, pick a place in the genome that you're interested in studying, order a piece of RNA, make

your your targeted crisper molecule and make a cut or a cut and a paste at that particular site and then in a very tangible way read out the consequences.

you're going into the source code of DNA inside of a cell and you can when you make that change you can say what what happens to the cell. Does it is is it a stronger response? Is it a different

stronger response? Is it a different response? We can test it in test tubes.

response? We can test it in test tubes.

We can test it in models of disease and then as we learn the rules we can actually take those crisper modified cells all the way and infuse them into patients.

>> Incredible. and thank you for that incredibly clear and detailed um explanation of the crisper cast 9 system. A couple of questions. How

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

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

I think what you're getting at with both these questions are unintended consequences and that's always present, right? I think this has been a major

right? I think this has been a major concerted effort for the field of crisper. How do you get more and more

crisper. How do you get more and more precise and it's come a long way, but nothing's perfect, right? So, I think we've done a lot the field has done a

lot of work to test offtargets, right?

If you're programming to cut on one place on chromosome 6, do you actually evidently accidentally ever cut anywhere else? And there's a range. Sometimes

else? And there's a range. Sometimes

some sequences are a little bit more promiscuous than others. But we've

gotten quite good at getting more and more precise to say, okay, we're making these high fidelity cuts that at at one place.

There are still the second risks of bystander effects. Okay, you make a cut.

bystander effects. Okay, you make a cut.

What does the DNA get chewed back? And

at the neighboring part, there's been in some extreme places pieces of chromosomes actually falling off. I all

these things can happen. And I think what we're kind of at a place in a field where now we're thinking about for each disease a risk benefit of okay, there's going to be there's always a risk for

any medicine of some unintended consequences. We have to be on the

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

problem. They just die off. So if you have an unintended consequence, most will die. But there is always the risk

will die. But there is always the risk of the unintended consequences. And I

think as a field, we have to be humble about that.

>> That said, the the the crisper world is not static. And what I what I the story

not static. And what I what I the story I told you was like the building block of crisper. It's a protein scissor that

of crisper. It's a protein scissor that can be targeted to any piece of DNA with an RNA molecule. people

are appropriately thinking well scissors can cause damage.

>> Maybe that that crisper molecule should actually be re-engineered not to be a scissor but to do other things. And now

people have started engineering it to say well let's not make it a scissor.

Let's make it a thing that just introduces a more predictable mutation at a site. David Louu at Harvard has created these things called crisper base editors that doesn't introduce a doublestranded break but actually

changes nucleotides in a more predictable way at that site by recruiting a damnase domain something that will change DNA nucleotides when it's recruited to a particular place and

you use crisper just to recruit that enzyme that makes that mutation at a targeted place other people have actually started using epigenetic enzymes that DNA doesn't just get

enacted by DNA sequences but can actually pieces of it can be active or inactive and this is called epigenetics where there can be a stable program of things getting turned on or off without

any change in the A's and T's and C's and G's and now we and other others are using crisperbased epigenetic editing it's called

epiediting where we don't make any cut in the genome but we just turn on or off and it's in a large part to think about mitigating some of these risk risks that might come with the scissor function.

Instead, all of a sudden, we're thinking about we're using the same building block of recruiting an enzyme to a particular place in the DNA code, but using the full set of things that we might do at that DNA site to program

cells in the most precise possible way.

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about getting crisper into the cells of interest. Yeah,

interest. Yeah, >> you know the lentivirus example that you gave before um my understanding is it involved harvesting some tea cells um

introducing the lentivirus with the you with the cargo that you want putting that back into circulation and the tea cells know where to go and know what to

do. uh for a lot of cell types like

do. uh for a lot of cell types like neurons in the brain, uh liver cells, pancreatic cells, um I could imagine a surgery where you

inject directly into those organs, but uh wouldn't it be wonderful if you could um get the cells of interest from, you know, without having to be so invasive?

Um so what's being done there in terms of trafficking um crisper 2 appropriate cell types or andor or organs and then that uh sort of

seeds another question that I'll I'll hold off on about whether we should be banking uh cells or or uh for what's coming.

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

>> No, I do too. I mean, you're taking us to the the >> I don't like the phrase bleeding edge.

sounds of violent, but you're taking us to the cutting edge of molecular biology and medicine and we are peering over into what's next like what your children

and my children and are probably our parents also will uh be able to benefit from in the next 10 years maybe sooner.

>> Yeah, we're really talking about things that are happening now and and happening at an accelerating rate. So you asked part of what just got made me have that reaction was I think you asked one of

the key questions for this field of how is this being delivered into cells. So I

told you let me go backwards and then I'll go forward. I told you that in 2012 I sort of was sitting there thinking about I wanted to study tea cells the genetic control of tea cells. I saw the

power of carti cells. They saw the power of crisper, which at that time was being only used in highly artificial immortalized cell lines that grow easily in the in the lab. And it just wasn't

clear that there would be a way to get crisper to work in real tea cells that you would take out of a human blood sample that are not immortalized that can only stay in a dish for a short amount of time and still retain their

function. And I put a I I sort of

function. And I put a I I sort of tripled down on this is what my lab was going to do. if we were going to figure out a way and we went through a long list of different ways that we might

deliver and it wasn't obvious actually a key collaboration early in my career was another serendipitous runin with I met Jennifer Dana through some persistence

of my own and Jennifer Dana and I sat down and started thinking about how could we team up to take her expertise in crisper 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 crisper protein. So we

had protein and RNA that would we we could make in a test tube. Now now we order it off the internet. We can mix them together and we could make these protein RNA complexes and we could

suspend that in liquid. And then what we did is we actually incubated TE-C 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

cells? And we use this trick that's been around for a long time. No one even as as long as it's been around. Sounds

magical and no one quite understands how it works. We put the cells into a device

it works. We put the cells into a device that gives a small electrical current to the tea cells.

>> Electroparation.

>> Electroparation.

>> Oh man, I I during my graduate career, I electroparated a lot of Well, I can just say it now because I don't do it anymore. Um, electroparate a lot of

anymore. Um, electroparate 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.

>> Yep.

>> And the assumption is that it creates little transient pores in the cell membrane and it gets in and sometimes you end up with four cells transfected and sometimes you end up with 40,000

cells transfected. It's a wildly useful

cells transfected. It's a wildly useful technique, but it's a little bit hit or miss.

>> That's perfect description. And so we we my first posttock in my lab Katherine Schumann sat there and tested different electroparation conditions altering these little pulse

>> pulse 12 pulses long pul you're taking me back to my graduate and and to some extent my post-doal years it's unclear for given tissues for given uh sequences what's going to go into cells what's

going to not kill the cells >> we were walking this tight rope of how do you make these pores big enough that crisper will get in but that the cells don't

And we did it, you know, and we did it.

And we've 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 TE- cells. And you know, we got our foot in the door with some level of

efficiency. We've gone through the roof.

efficiency. We've gone through the roof.

This is now used by labs widely and it's incredibly efficient. And some cells

incredibly efficient. And some cells die, but overwhelmingly you end up with cells that that are gene edited.

>> She figured out the protocol.

>> Yeah, she really did. And it's been optimized. And then another grad student

optimized. And then another grad student in my lab came in, this guy, amazing grad student Theo Roth, and realized that he didn't have to stop there. That

we thought we were limited to just putting crisper in and these very small pieces of DNA called oligoucleotides that were just change a couple of nucleotides at a time. Our mindset was like, maybe we can fix a mutation, an

individual mutation. Theo said, let's

individual mutation. Theo said, let's not stop there. let's put big pieces of DNA in. And we've pushed this boundary

DNA in. And we've pushed this boundary of being able to say, let's pick a site, make a cut, and introduce hundreds or up to thousands of different nucleotides to be able to really write a piece of DNA

code that doesn't even have to exist in nature. But then we have the precision

nature. But then we have the precision using crisper to put it into a particular place in the DNA. We started

a company when that when that technology worked, a company called Arsenal Biosciences that's now in clinical trials. It's actually it's in its clin

trials. It's actually it's in its clin third clinical trial right now for solid tumors. It's in a clinical trial for

tumors. It's in a clinical trial for prostate cancer that's about to start enrolling patients. And that company can

enrolling patients. And that company can now do this at industrial scale. It

takes patient cells, electroparates them, and has now written a long piece of like 10 10,000 nucleotides of DNA

code that put in a sequence of a combination of different receptors, including a car and additional gene enhancements that will make these tea cells more powerful in in in a tumor

micro environment.

>> And then they go into the bloodstream, they navigate to the prostate >> and they start fighting the cancer cells. And I imagine you can also put it

cells. And I imagine you can also put it sounds like you're putting some um kind of resilience genes in there as well to bolster the healthy cells >> to bolster the the tea cells that carry

these receptors to make them persist longer and be able to fun. Exactly.

>> Awesome.

>> That's happening. And you know that that the way that that happens is that a patient will be selected will go in for a blood donation, give a rather large

blood donation, but those cells are then shipped to a facility that Arsenal maintains. The the electroporation

maintains. The the electroporation happens in the centralized facilities.

The cells get grown up for a couple of days and tested. They get frozen down and then sent back to the patient where there the cells are then thawed and they get it's the equivalent of a blood

transfusion. Now their own cells have

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 crisper castine, they're sitting in this bag um that get infused. Are they

designed is the crisper designed to to only go after the prostate cancer cells?

Um, or is there some version of this where you can inoculate against a number of different cancers? In other words, if I'm understanding correctly, if there

are sort of um canonical >> mutation sequences yeah >> that occur in all cancerous cells. Yeah.

Is there a version of this where I give some blood >> you or a company probably a company electroporates them with uh the crisper

cast 9 system brings in resil resilience uh genes for the te- cells from my te- cells um plus some attack genes right so

that are going to destroy the cancer cells and then I get an infusion of these when I turn I'm 50 now so like 52 and then it protects against all cancers that probably are forming at multiple

sites throughout my body. Low mutations

here, low mutations there. Hopefully

they don't, you know, proliferate. But

is there a way to just short circuit cancer bodywide?

>> 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 an

unproven technology >> is tolerated. And you know, I think that 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 that that's where we start.

>> But our hope is that these technologies eventually will be proven to be safe.

They'll get more and more precise. I

hope the cost would go down. And I don't know, you know, you you talk about the other extreme of doing it preventatively, but at least we should start marching earlier and earlier in

the course of diagnosis. And the hope is that, you know, there'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. Um, I think to get there,

even better. Um, I think to get there, if we really want to scale up, I think we also have to think about you sort of going back to your last question about delivery, maybe it's not always going to

be these cells getting shipped to a centralized factory and electroparated.

>> Um, 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 a

Immunology. We're starting a philanthropically funded crisper trial for multiple myyoma where we're using a different genetic program. So we we 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 that the deliveries of the future will happen and different people are 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 crisper in these targeted ways with electroparation. What

if we could put crisper into the body and just send it and address it >> just to the cells that we want to modify? We're interested in the tea

modify? We're interested in the tea cells.

>> Someone else might be interested in modifying or heart or neurons 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 a posttock there was it was all about it seemed for a few years like different ways to get genes into cells. Um, so there's

into cells. Um, so there's electroparation, there are lentiviruses, there adnoiruses, there calcium phosphate transfaction, there was and on and on. One of the things that was kind

and on. One of the things that was kind of interesting, but at the time didn't really go anywhere was um customized little uh liposomes like little fatty bubbles. Yeah.

bubbles. Yeah.

>> Cuz fatty stuff can get onto and through cell membranes. So it makes good sense.

cell membranes. So it makes good sense.

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? The

liposome technology >> dramatically.

>> Oh great dramatically.

>> Relieved to hear and relieved to hear I wasn't the one that had to do the work because I knew a lot of very frustrated people working on liposomes. Fortunately

for me, electroparation adn noiruses worked spectacularly well for my experiments, but a lot of people needed cell type specific in um transfaction.

>> Yeah.

>> Through a a vein injection.

>> So all of these things have gone under rapid progress. The vir let's talk about

rapid progress. The vir let's talk about the viruses. We talked about viruses as

the viruses. We talked about viruses as a tool to as a shuttle of DNA.

>> They naturally each one will have some range of what cells it would infect.

This is for a virus. This this is called tropism. What is what cells are

tropism. What is what cells are susceptible to infection with any virus?

Those would be the cells that you would be able to deliver genetic material to with an engineered virus. People have

really advanced engineered tropism.

Engineering what cells a virus will deliver material to. And that can be dialed in quite precisely now in a number of different ways. So people are working on engineered viruses that

>> trying there's still problems. trying to make sure that they don't trigger immune responses. But they're getting more and

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

tropism is. And that and people are working on engineering these tropisms with a lot of technologies >> because you could put drugs in them too.

I mean, we talk about, you know, like SSRIs have all these side effects. Well,

that's because you're getting serotonin uh, you know, increases at locations you don't want it. Like you could imagine only getting drugs to certain cells.

It's it's super to me it's super exciting and just seems 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 targeting. Now, you asked about lipid liposomes.

>> Now, liposomes have kind of come up with our new name is lipid nanoparticles. the

banana particles that kind of rolls off the tongue nicely.

>> And you know the abbreviation we use is L&Ps but a billion people around the world have now been injected with L&Ps.

L&PS are the technology that delivered mRNA vaccines.

>> Ah okay that'll raise some eyebrows.

Yeah. No, we're going to talk about vaccines. Listen, we're going every

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.

This was done locally for the co vaccine, but people are now engineering them with the targeting molecules that he described so that they go to particular cells. If you inject them

particular cells. If you inject them into the body, lipid nanop particles naturally tend to go to the liver. So

people are using these already to cure genetic diseases that where the genetic burden is affecting the cells in the liver because you can deliver crisper to cells in the liver pretty robustly with these.

>> I have my strong view on on the COVID vaccine. I think it was a miracle that

vaccine. I think it was a miracle that we were able to develop something on a short timeline to address a pandemic that was killing killing people. But

I understand there's controversy.

Leaving that aside, lipid nanoparticles are it's amazing that we were able to do this that we took something that was an idea. Most people thought it would be an

idea. Most people thought it would be an obscure technical thing like you talked about like it would would it ever work?

All of a sudden it could be manufactured at scale. could deliver a synthetic

at scale. could deliver a synthetic piece of of mRNA to give a temporary instruction to cells to make a protein to protect us. And whether that's for CO

or for other things, all of a sudden we're 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 about something totally different. We're talking about

different. We're talking about delivering crisper. not the an mRNA

delivering crisper. not the an mRNA vaccine, but we're talking about how would we get crisper 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 nano particles that could be injected into the bloodstream. Think of them as these

bloodstream. Think of them as these little fat bubbles exactly as you said, but in them they they included a protein that would recognize something on the

surface of tea cells. So that as these lipid bubbles were going through the blood, they would stick preferentially to tea cells and deliver mRNA to TE- cells. And you could actually put in an

cells. And you could actually put in an mRNA into TE- cells that would temporarily make a gene that it would encode a CAR, these artificial receptors

against cancer. And they've done this

against cancer. And they've done this now in testing in a number of models.

that can actually make these CARTT cells by inject injecting lipid nanop particles into the body without ever taking the tea cells out of the bloodstream. And I think we're going to

bloodstream. And I think we're going to see more and more things like that. The

farm industry is all of a sudden saying, "Oh, there's more ways that we can make drugs. Things don't have to just be

drugs. Things don't have to just be pills anymore. They can be engineered

pills anymore. They can be engineered proteins or lipid nano particles 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. Yeah. Um because in my role as

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

>> Um and I can't speak for everybody. Um

certainly, but I think that at least three of the things that caused a lot of divide around um the the mRNA vaccines

were first of all um the difference between mandates versus optionality. We

don't have to go there, but I think that that that was a that was a major player, right? People, especially Americans,

right? People, especially Americans, don't like to be told what to do.

>> That's just I've noticed that. Okay.

Second of all, um it was closely related to um notions of the shutdown which differentially impacted people. Um and

that's an understatement, right? Some

people maintained paychecks, some people didn't. Some people could work, some

didn't. Some people could work, some people couldn't. So, there was that. I

people couldn't. So, there was that. I

just I I'm not trying to uh you know, soften anything here, but I think that the the vaccines were were nested in a bunch of other issues. Um again at least three this is not exhaustive. And then

the other one and I actually had this concern myself which was how is it that it gets turned off right like I I can

imagine a situation where I would want to put uh an mRNA into me um to do something biologically but then I don't

want it to continue to do that after a period of time. So what in the design of that vaccine allowed it to be targeted to the cells of interest and then not

continue to express in all other cells in perpetuity?

>> I'll answer the specific question but I think that the context that you give is also a really important part of this and I I'll take one second to talk about this. I think to to to answer your first

this. I think to to to answer your first question we talked about DNA as the the sort of source code. We talked about proteins as what the DNA is ultimately

encoding. Let's just talk for a second

encoding. Let's just talk for a second about what mRNA is. mRNA is the sort of temporary intermediate between those

things. DNA will get what's called

things. DNA will get what's called transcribed into mRNA which is a another nucleic acid but doesn't stick around permanently. It is the temporary

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 some 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 co virus very small part right now just by comparison if you get infected with covid you're also going to get co mrna is transcribed in your cells

and you know that that that so there's we're talking about genetic material making mRNA either way whether it's the mRNA from the covid or a designed small

part of that co vaccine that of that co genome that we're using as a vaccine. So

I think it's important to think about the risks in the context of the virus versus what we're doing with a with a vaccine. So I got the COVID vaccine

vaccine. So I got the COVID vaccine enthusiastically and I and I actually I think overwhelmingly my imun I mean I know overwhelmingly my immunology colleagues did the same in people who

live in this world of immunology a a great enthusiasm that this could be done and built. Now what that doesn't answer

and built. Now what that doesn't answer what you said about the cultural phenomenon. I'm talking just as a person

phenomenon. I'm talking just as a person not as an immunologist but >> I think we probably haven't done enough to talk about the trauma that we went

through as a nation during co of >> being fractured by people dying on one hand and all the negative consequences as you said of of shutdown shutdown of

economic life shutdown of social life. I

I I think it was a period of major dislocation and we're still feeling the trauma and the people's different relationships with things like vaccine

but of science even more generally were dislodged or accentuated by this trauma that I think we all collectively went through and we don't talk enough about.

>> Um I'll just give one anecdote. Well, I

I spent a lot of time isolated during CO and was disheartened by the fact that on one hand I was watching the sort of scientific like speed race. That was,

you know, actually, I think, one of the one of the the highlights of of the first Trump administration, Operation Warp Speed, to to streamline and get coordination both on the science and the

the regulatory side to get vaccines approved in an extraordinary timeline, taking advantage of a number of technologies and making them all. So, I

was watching this this science unfold with some some optimism, but also watching the trust in science being eroded. I developed it aside hobby um

eroded. I developed it aside hobby um which is I've been I've gone back and I've been reading I've been reading presidential biographies sequentially

this is this is it's just a side hobby now in this in reading in thinking about this sort of frustration with with how science was sort of tearing things apart

I found this sort of strange relief in reading about early American history in 1793 there was a yellow fever epidemic in in

in u in Philadelphia and actually the early parties that were forming the the Federalists and the Democrats actually took like wildly dissenting views of how

to deal with an epidemic. They they had different views of what caused it whe whether it was outside contagion or those or sanitation. And the the Democrats at that time, the Jeffersonian

Democrats were in favor of like really extreme uh bloodletting techniques and the and the Hamiltonians, the Federalists had it had a totally

different set of techniques of baths and 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 in that that these discussions of how we deal with infections which are inherently societal diseases unear the societal tensions and

we deal with them in different ways and we come to them from different perspectives and there there's a lot of things that are simultaneously being balanced in any decision of how we deal

with thinking about the trade-offs that we're willing to make in the face of of an of a pandemic or an epidemic.

>> I really appreciate that and I'm also impressed that you're reading these biographies. How do you know which

biographies. How do you know which biography to select because there are many of them and unfortunately Walter Isacson hasn't written them all. I love

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

>> This is this is an this is a a project that I spend a lot of time each one I I go through a period of indecision about which one I I should read.

>> I can share my list. I'm not I'm not done yet. This has been over several

done yet. This has been over several years. I've been I'm now up to World War

years. I've been I'm now up to World War II.

>> You should do a podcast someday. Just

know in your copious amounts of spare time, not as a husband, father running a giant lab, etc. and physician, uh you could do a podcast and and teach us what you learn. Anyway, awesome. I'd like to

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a question related to technologies to killing or altering cells that we didn't cover but since uh we've touched on a number of them the uh lip lipid nano

particles um lenty viruses since we're um in a previous lifetime I used uh in my experiments and I was excited by

immunotoxins so an antibbody against you generally need a cell surface protein and then you attach to it in our our case we Saporin toxin, which uh I think

is most infamous uh because it was put on the tip of an umbrella and used to assassinate somebody on a bridge someplace in some sort of uh

international spy warfare in the last 20 years or so. Saporin will kill you if it goes systemic. But the idea there is

goes systemic. But the idea there is that you take the Saporin toxin and you tether it to an antibbody 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 thoroughess. Um

has that been tried in cancer um directing toxins towards uh cancer cells?

>> The short answer is yes. It's a it's a really interesting area and and and what that toxin is can almost be thought of as like modular that you can put put a

different that you can think of it as two components, right? You have a targeting component. You have in an

targeting component. You have in an antibbody is a natural one where an antibbody is evolved to recognize one particular type of protein that can be

the thing that targets something on the surface of cancer cells.

Um people have then developed what's called antibbody drug conjugates where basically a drug or a tox something that's going to kill the cell gets

appended to that antibbody and so it's selectively delivered. You don't have to

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 antibbody.

>> Doesn't have to be drugs. People are

thinking about other things. we were one people are now trying to attach uh radioactive isotopes there's radioan therapies that to the that can be

attached to these things um and I think in an extreme that's essentially what we're doing with these T- cell therapies too >> we're also using the the when I I've

talked about this CAR the chimeic antigen receptor the outside of it that is the sensor that's being used is also an a part of an antibbody and so essentially what we're doing is now

using the antibbody to target, but instead of dra 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 the cell not the

killing module. But the the cell not the T- cell not only kills the cancer cell, but could potentially be used to amplify that response, could recruit re-release things and recruit other things. So I

think this general way of thinking about designing things um to drag something to a cancer site is something that people are thinking a lot about. There's even

another flavor of this that are called T- cell engagers. So I talked about okay we can genetically put an antibbody 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 bispcific or a bite. The bite is a proprietary term. Um but basically these

proprietary term. Um but basically these are two-headed antibodies. One side will recognize a cancer cell and the other side will recognize a T- cell and essentially bring these things together

so that you get the T- cell action locally to the cancer cell without having to do any genetic mod modification to the T- cell. You

actually just take advantage of TE- cells that are already in the body. So

all of these things are now under very active developments and 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. Yeah. and you can um put all sorts of interesting cargos and play matchmaker between cells and um it's

kind of infinite what what you can do um once you start to understand things at that scale. That's really what it's

that scale. That's really what it's about.

>> I'll push it one step further. I'm

actually uh helping to organize a cancer amunotherapy conference here in in LA.

I'm 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

I'm an adviser to Amgen but this this talk was and Amjen's been one of the leaders in these bites I think they actually trademarked this idea of bicep

specific T- cell engager um these are antibbody fragments but one of the leaders at Amgen talked yesterday about how looking forward these aren't being

used as just traditional antibodies that come out of of animals, but they're actually being used as AI designed protein engagers of any target you want.

So essentially now it's getting to the point where if you know that something's on the surface of a cancer cell, people are increasingly using AI models to

design a synthetic protein that doesn't even exist in nature that is designed to recognize and stick to something on the surface of cancer cell. And that could

be of one of these Lego blocks for these modular multi multiaceted in cell engagers or drug engagers or any of these other things. So this

is another area where the the cross talk between experimental capabilities and computational exper capabilities is further accelerating what's possible.

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

>> No, I I would love it.

>> I'll keep this brief. Um a few years back uh we all learned meaning the entire world learned that uh a scientist in China had done a crisper cast

experiment on babies.

>> Yeah.

>> I don't know when he did the modification. My guess is it was in

modification. My guess is it was in uterero. you'll tell us what exactly he

uterero. you'll tell us what exactly he did. This hit close to home for me

did. This hit close to home for me because he and I were postocs at the same time at Stanford different labs and the way it the news hit the world was

very interesting. One of the things I

very interesting. One of the things I benefit from now as a podcaster and not just a professor is that I can talk about the stuff that perhaps pure professors wouldn't be willing to. Um,

so I'll say it. It was very interesting because the world kind of braced but didn't make a decision as to whether or not they were upset that he had done this like put him in front of an ethics

board, maybe even throw him in a cell or give him a Nobel Prize. It was like there was this kind of moment where no one really knew what to do.

>> Yeah.

>> Like do you reward him? Do you punish him? Do you do nothing? And it

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

colleagues. I think we didn't understand how to react to this. And then the decision was quickly made at large that he had done a bad thing.

And that's kind of the last we ever heard about him were those kids. The

Chinese government condemned it publicly. Uh I think they said he was

publicly. Uh 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 um given a larger laboratory and more

resources. It was very unclear.

resources. It was very unclear.

>> It's playing God at some level, right?

It's not the same as deciding to not implant some embryos that were created through IVF because they carry an extra chromosome. It's different than that.

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 um crisper in 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'm I wasn't there but there was

moment. I'm I wasn't there but there was a international crisper conference that was being held I believe in Hong Kong at

the time and the the scientist um got up and announced with extraordinary pride in in in one of these sessions in this conference that he had done it he had

done genetic modification of embryos and my understanding of what what had happened was that there were two twins

um who were There there was were parents who wanted to have kids and the father was HIV positive and the modifications that they decided

to try to make were to delete a gene that is if it if it's deleted can confer resistance to HIV.

>> This is a gene called CCR5. there's

people who naturally have a certain mutation in this certain at some frequency and mutations in this gene confer resistance to HIV if they're naturally occurring. So that was the

naturally occurring. So that was the supposed rale.

>> So there was a disease um 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 from 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

embryo. So I think it was a bit of a manufactured need but there was this supposed justification.

Second of all, it was done um so they actually ended up generating two twins and my understanding of how it was done and I don't think that this was ever

published. There was some some publicity

published. There was some some publicity that was released. So I'm sort of piecing this together from what was public at that time, but I don't think any journal ever published this in any

peer-reviewed context. Um they did this

peer-reviewed context. Um they did this in concert with essentially IVF techniques. So they were fertilizing

techniques. So they were fertilizing embryos with this with this father's sperm as the mother's the mother's eggs.

They created multiple embryos and then they delivered crisper into these embryos and trying to create mutations in the CCR5 gene.

There was some variability. It was

pretty early in days of crisper and as I said there's an unpredictability of what happens when you make a double stranded break in the genome.

It was a stretch to say, okay, they didn't exactly get the mutations that they wanted, but they proceeded nonetheless to implant these embryos.

And I know less about this, but there were also serious concerns about the way that consent was done on this, like how much was informed about what the actual

benefits would be to these patients. My

understanding is that he got up and I wasn't in the room, but I do think that there was some degree of immediate horror that this was being announced and that that it was unfolding in this way

and that it hadn't been considered. It

it was it was not ready. In the wake of that, the Chinese government then announced that they were going to punish this and I don't know the details, but I believe that he unders underwent some period of house arrest.

>> Okay. He he was punished. I believe so after I I think after there was some degree of scientific outrage at this point.

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

>> Okay. Well, you're clarifying a lot of the the detail important details, >> but my understanding again is that he's now free and I think is is restarting a lab. I don't think in

China. I think somewhere else. Um so the

China. I think somewhere else. Um so the story might not be over yet. Mhm.

>> So that's my understanding of of the facts.

>> Let me 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 I I told you I've dedicated my life now to creating crisper technologies to engineer individual cells in the immune system. But these

are what we call sematic 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 ed

we're not making genetic edits in sperm or in eggs.

If you do it in an embryo, all of a sudden every cell in the developing embryo will 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 imagine to make an enhancement. People have

talked about you know maybe you want to add we know genes that would make people be more muscular or will there be a rush to you know >> or enhanced 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 um introduced maybe a mutant or an extra I've forget now it's been a

while um case in point I clearly don't have this receptor uh to uh 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 that made quite a splash at the time I forget where that went and may maybe Joe followed up on that. I

don't know. But um 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 um memory genes?

>> Yeah.

>> But of course, we have no idea if that's a good or a bad thing. Forgetting

certain things is very useful as well. I

completely agree with you and I and I think the point you made is a key one that we do have a we we do live in a world where people do IVF and we do pre-implantation genetic testing and we

select in people opt people have the option to select non-implant embryos that have certain mutations that's already a level of like avoiding disease in in a next generation if there's a

severe mutation I think it's not it's it's a qualitatively different step to then not to select but to actually make a genetic change. All of a sudden now

you're really hampering you're you have the ability to make some kind of mass- prodduced genetic edit in many embryos. I worry a

lot about what this means for our offspring if they are designed rather than just born by by chance. I worry

about fads. You know, when 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 can order those in in concert with IVF. And I I don't think we gain

with IVF. And I I don't think we gain enough to to come close to what we would lose as a society if we embark on that

journey of of editing offspring.

>> Appreciate the clear stance and and answer. Uh as long as we're there, I'd

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

an important caveat for deep sequencing embryos from IVF. So typically with IVF check to see that they're chromosomally normal, that they're uploid 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 um industry now, I believe a company in the Bay Area, Orchid, um is is probably the most popular uh one or well-known one uh where

>> if you pay a certain amount of money, they'll um deep sequence. If you pay more, they'll deeper sequence. Um, and

so you're getting some additional readout of potential disease genes and and I I've looked at that technology and they're very clear that they at some point they can't draw a causal

relationship between say like a neurolyan mutation and autism but there are these implications based on the animal data or and so it it starts to

become this it's not gene editing.

>> Yeah. But it is a deeper and deeper uh gene sequencing based selection of embryos.

>> Yeah. First of all, I'm I'm sympathetic to the idea, right? Like 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 a chromosomal abnormality that would really impair lifespan or quality of

life for your offspring.

I the imp impulse that we know that's this the sort of straightforward chromosomeal testing that's done at from the first level does will miss a lot of mutations. So people I understand the

mutations. So people I understand the idea of trying to fill that in with more deep sequencing or comprehensive sequencing of the genome. The problem is there are some mutations that if we know

if we see them we will know that they can be cause severe disease but there's a lot that are become probabilistic and statistical and I think we're

overpromising what can be delivered.

>> 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 there's

others. And I think the fact is there's just a it's not an access that actually exists. there aren't categorically more

exists. there aren't categorically more desirable or less desirable. We want

diverse diverse people for and you know how successful you're going to be as a interplay of like how your genes inter come around and influence your community your your environment those are

unknowable from just looking at a DNA sequence alone. So I think that there's it

alone. So I think that there's it introduces a false axis. There's another

book that I I would would recommend here that I read years ago and I actually I'm probably overdue to go back and and reread this. This predates crisper

reread this. This predates crisper technology, but there's a Harvard philosopher Michael Sandell who years ago wrote a short book called The Case

Against Perfection. And it's a really

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 chance and happen stance which is like a part of our

relationship with with our kids with ourselves of thinking like okay this is this is the human experience of you're a product of some degree of chance and and circumstance.

I'll definitely check out the book. Um I

I know the whole point of life is not to be a quote unquote high performer, but I I'll just say as an example, um I know of no single very successful person that

doesn't have some thing about themselves that um that initially they disliked or felt that they had to overcome which led them to pursue certain things hopefully

in a healthy way. um and that they eventually came to embrace and is now and are now grateful for. I I know of no exception to that. It's just kind of it

it's sort of the story of of humans in many ways. It's a story of humans and in

many ways. It's a story of humans and in fact uh uh people who perhaps are told that they're perfect in every dimension their entire lives. Um they I can only

imagine the amount of pressure they must feel. In fact, before today's

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 are hardships or or disabilities often end up being the things that that make us who we are and

and you know, make us more sympathetic, give us added depth as humans. And the

things that we think are the things that make us perfect are the things that are really holding us back or creating all sorts of false ideas that limit us.

>> I couldn't agree more.

I'd love to know what right now you're most excited about for your own intellectual enrichment and in your lab and and like what you really feel is

like the the thing that has the most electricity for you. and and if you're willing to also give us a a hint of what's just right over the edge in terms

of what you think will be the next big therapeutic breakthrough um that we can look forward to.

>> Thanks for asking that. So I'm going to give a little bit of a long and meandering answer that >> I mean listen when it comes to me you don't have to succinct is not something that sort of like exists in my neural

circuitry although I try. So I see this this moment I talked about clinical trials where that are already filling me with hope. I talked about a a biotech

with hope. I talked about a a biotech trial that I'm associated with for prostate cancer. I talked about an

prostate cancer. I talked about an academic trial that I've put a lot of work in with my colleagues over many years to open for multiple myyoma. And

we have a pipeline that we're developing.

We didn't even talk today about we we haven't fully talked yet about the idea of CARTT cells for autoimmunity. We left

that open a little bit, but that's an amazing moment that we're at right now that the same CARTT cells that are being used to get rid of B cell leukemas are also getting rid of B cells which are contributing to autoimmune disease. So

without making any change, people are already starting to see incredible responses in the early trials for lupus and other autoimmune diseases with tea cells engineered to eliminate B cells.

Oh, >> fantastic. Could you just mention a few

>> fantastic. Could you just mention a few other disease targets? I I know a few people with fibromyalgia. Um they suffer tremendously.

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

don't understand. Like that is that is >> talk about underststudied diseases. is I

think fibromyalgia is something that gets bucketed in a certain way and we just have not figured out what what is what it really is what what causes it and so my that that is its own thing but

for autoimmune diseases these are diseases where we do know that there are immune cells going after our own tissue in various ways lupus people are talking

about various engineered te- cell trials for rheumatoid arthritis for childhood diabetes for multiple sclerosis um and on and on but those are a number

that people are thinking about different types of immunotherapies including gene and edited tea cells to treat these autoimmune diseases. So I'm already I

autoimmune diseases. So I'm already I guess what I'm saying is excited about the near future of things that have come

out of decades of lab work from labs around the world already starting to be assembled into things that are advancing through clinical pipelines. But the next

wave of what's coming up behind that is just as exciting if not more. So I think that one of the things that makes me feel like I I have one of the great jobs

out there is I there's about 30 people in my lab.

I get the joy of ideas bubbling up. They

don't the idea of the lab don't come top down from me. They come from grad students and postocs who have come filled with energy to bring their own ideas and progress is being made through

this conversation of people in the lab reading papers going to conferences talking late at night in the lab and I can't believe the surprises that are

that are coming. So I I want to give you a couple of these. So I just look looking backwards to 2013 2014 we were struggling to see if we could get crisper into with

electroparation to make one cut in a T- cell. We could barely do it. Now if a

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

crisper experiment where we do crisper where we deliver a set of thousands up to tens of thousands or hundreds of thousands of different crispers into a population of tea cells from a blood

sample. So each cell will get a

sample. So each cell will get a different crisper 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 the type of genetics that was

possible in fruit flies but unimaginable in human cells we're doing directly in the human cells that will be the therapies of the future. We're directly

learning what are the genetic modifications that will make tea cells do exactly what we want. And one of the things that we just made publicly available is that we used to do these

experiments and race these cells against each other and read it see race them against each other for one characteristic which ones would start to

make one cytoine. 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. We this is a technology called single cell RNA

sequencing. So we measure now

sequencing. So we measure now simultaneously all of the the RNA that's in that cell telling us giving us a snapshot of what that cell is now able to do. And we can also simultaneously

to do. And we can also simultaneously measure which crisper was put into that cell. And so now we can essentially

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 directly in primary human immune cells.

We just released 22 million cells where each one has a different crisper gene inactivated. And we get a map of this.

inactivated. And we get a map of this.

And I think of this not just what we're doing in T- cells, but what other labs are doing around the world, using crisper to read out the consequence of every gene in different cell types, in

different conditions as a sequel to the genome project.

>> You know, we talked about the genome giving us this draft of the DNA sequence. Now, we can actually read out

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

every cell. And this is being used with in as a basis for massive computational analysis. It's providing us a a real

analysis. It's providing us a a real road map of how cells are wired. That

will be the instruction manual for the next generation of T- cell amunotherapies. That the lessons that we

amunotherapies. That the lessons that we learn about how every gene behaves are now going to be actionable. And these

are going to be genes that we tune or epigenetically edit or inactivate or add to genes that we will now have a recipe book for what what do we want an immune cell to do? What do we want it to

recognize? What where do we want it to

recognize? What where do we want it to go? And we'll have a cheat sheet

go? And we'll have a cheat sheet >> that tells us, okay, here's 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. Um,

should I be banking tea cells?

>> Well, I think the good news is that that's a I never know what the answer is.

I was going to say the good news is that we largely have tea cells. Now there are are there exceptions to that? Yes. You

know there are patients who are getting treated for certain types of cancer and the the chemotherapy that they're getting depletes their tea cells.

I it's hard to know, you know, I guess I I can't say that there would never be a use, but I think we're getting better and better at being able to take whatever tea cells are there and and I

hope reactivate them, re endow them with powers.

I would be disappointed if in the future we would need to go back and take bank tea cells and not be able to re-engineer cells that are already there. Are there

edge cases where it might be? It's not

something that I would tell people to go out and do. I It's not something I'm doing.

>> I Yeah, I would only do it if you told me to. uh a colleague of yours um

me to. uh a colleague of yours um Yamanaka won a Nobel Prize for essentially showing that you can take a skin cell put in a dish give it Yamanaka factors as it were 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? um reverting them to the

ready state? um reverting them to the stem cell state. I in my mind I always thought well if I ever need more cells of a given organ I can always assuming I'm I'm alive they you know they can

take a skin cell and they can do all that but I could imagine that there would be use for a cell bank not a tissue bank where there are a bunch of

these pur potent >> huberman in my case Marson in your case obviously uh cells that if uh you know god forbid I needed a bunch of pancreatic eyelet cells Boom. They could

have those within a week.

>> This field is is something that's been amazing to watch. It's it's there's been ups and downs of it of this induced pur potent stem cell field that Shiny

Yamanaka opened up. Um, one of the interesting areas is actually imagining how these IPS cells could be made into tea cells which would essentially create a limitless supply of T- cells.

>> That's what I was thinking. You know, I don't you don't have to even draw blood.

>> Exactly. which would negate the need for banking if you had your so I don't know if again it's probably not something that I would be cost effective for everyone to have their their IPSLs are

ready to go I understand from in conversation from from with Sheny Yamanaka that one of the things that he has been involved with is actually building sort of a bank of IPS cells

that would be compatible immune compatible with broad sets of different people so that it could essentially be used as a transplant bank which would might be a way to be like an intermediate step that there would be

IPSLs available that could be transplanted with various degrees of ease into different people >> and then I do think that I hope it gets easier and easier to make IPS cells that

are matched to any patient when they're needed. So, but I mean again like this

needed. So, but I mean again like this these different threads of things of being able to make endless supplies of any cell, direct them to any

tissue type and then being able to program them when the language of crisper actually it's worth some moment.

I in 2020 I moved my lab from the main branch of UCSF to a separate research institute in San Francisco called the Gladstone Institutes. It's a nonprofit

Gladstone Institutes. It's a nonprofit research institute. My grad students

research institute. My grad students still come from UCSF at University of California, San Francisco, but my lab's at Gladstone.

And one of the reasons that I moved my lab to Gladstone was a conversation when they when they were recruiting me, they brought me into the president's office.

And in in the president of Gladstone's office was Shina Yamanaka, who maintains a lab at Gladstone, and Jennifer Dana, who also maintains a lab at Gladstone.

you had to say yes. They're very clever that you had some psychologist uh inform that they got your number so to speak.

>> I described this and I think this not just a cliche. I actually remember kind of like that feeling of hair sticking up in the back of your head of like oh all of a sudden these are the technologies

that the these two humans have made possible and and others. But we can now program the what the epigenetic state of a cell is. Thanks to the Yamanaka

factors, you can dial between skin and embryo and and then back to anything else and then not only epigenetically program a cell, but take the power of crisper 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 the body and get to the root cause of disease.

And I my imagination still lies at that intersection of what's possible when we combine that with immunology.

>> I love it. I one question I don't expect you to answer, but uh your enthusiasm for this uh 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. Like the tools are are they're here. Um and mostly I want to say thank you. Um, 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

autoimmune diseases. I mean, we got into molecular biology with some considerable degree of depth and thanks to you, it was incredibly clear. I know people learned a ton. I know I learned a ton

and I'm super excited about what you're doing. Also, just the the heart and

doing. Also, just the the heart and soul. There are no other words really.

soul. There are no other words really.

Um I think those are are apt. The heart

and soul that you put into your work is so clear. Um and you are definitely in

so clear. Um and you are definitely in the right job. So just uh one request is that you come back and talk to us again um when the next advancements are made.

We'd love to have you back.

>> I'd be honored. And I just I just really want to thank you. There are not enough forums that are dedicated really to the depth to talk about science. the 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 it's an honor to be here.

>> Oh, well, thank you. Um, it's a labor of love and I've loved this. So, come back again.

>> Thanks.

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