We're living in this amazing moment of

biology where we can put a gene that

encodes something on the surface of tea

cells that will make them programmed to

search and destroy for cancer cells.

>> Now this is largely known as CART tea

cells, chimeriic antigen receptor. This

is a receptor that was designed in a lab

does not exist in nature. When those tea

cells get reinfused into a patient the

way that you get like a a blood

transfusion, those cars are directed to

go against cancers. Welcome to the

Huberman Lab podcast, where we discuss

science and science-based tools for

everyday life.

I'm Andrew Huberman and I'm a professor

of neurobiology and opthalmology at

Stamford School of Medicine. My guest

today is Dr. Alex Marson. Dr. Alex

Marson is a medical doctor and scientist

at the University of California, San

Francisco. He is developing new ways to

reprogram the immune system to cure

cancers. Today we discuss how your

immune system works, how autoimmunity

works, and how gene editing and other

new technologies can be successfully

leveraged to defeat childhood and adult

cancers. Dr. Dr. Marson is truly one of

a kind in his understanding of the

clinical aspects of cancer treatment,

the science of the immune system, and as

you'll soon hear, in explaining the

things that genuinely increase your

cancer risk, many of which are

surprising, and the actionable steps

that we can all take to reduce our

probability of getting cancer. In

addition to the usual factors, smoking,

UV light, and environmental toxins such

as pesticides, we discuss the actual

cancer risks that come from things like

eating charred meats, airport scanners,

and food additives, and how to gauge

your individual level of risk. We also

explore gene editing for reversing

diseases, which until recently was

science fiction, but now is a reality.

By the end of today's episode, thanks to

Dr. Marson, you'll have the most

up-to-date understanding of the

state-of-the-art science for cancer

prevention and treatment. Knowledge that

is certain to impact you or a close

friend or family member in your

lifetime. Before we begin, I'd like to

emphasize that this podcast is separate

from my teaching and research roles at

Stanford. It is however part of my

desire and effort to bring zero cost to

consumer information about science and

science related tools to the general

public. In keeping with that theme,

today's episode does include sponsors.

And now for my discussion with Dr. Alex

Marson. Dr. Alex Marson, welcome.

>> Andrew,

>> this is the first time that we're going

to have a serious discussion about the

immune system, cancer, and gene editing

technologies on this podcast. So, I'm

delighted that you're here. It's also

great to see you again.

>> Thank you for having me. Really, really

good to see you.

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

the big picture.

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

biology looking? How's medicine looking?

Are we uh are we on the fast track to

much better things? Are we going to slog

along for another 10 years before we

have cures to the many concerns that

people have about cancer, Alzheimer's,

and the rest? Or are you encouraged by

what's happening right now?

>> I think maybe there's some some the

general public doesn't quite know how

excited biologists are about what's

possible. And maybe we've overpromised.

Maybe in the past we've said we're on

the brink of curing disease and people

haven't seen it. But something is

materially different right now. And

there is a convergence of so many

different ways of understanding biology

but then not having that stop at

understanding but to actually intervene

and at the root causes of disease. And

over the course of this conversation, I

imagine we're going to talk about DNA

sequencing,

understanding cells, but going all the

way to rewriting specific DNA sequences

inside of the cells of our immune

system. Doing this not one at a time,

but testing every gene and understanding

pieces of DNA throughout our entire

genome to understand what controls our

cells. and then being able to take that

information and actually do something

about it to boost our immune system to

go after cancer to balance it for

inflammation and autoimmunity. And that

doesn't just have to be sort of

searching for a pill. All of a sudden,

we can actually talk to our own cells

and give them instructions in the

language of DNA and the language of

molecular biology. And in some

instances, this is being done with

crisper, but it's also being done with

lipid nanop particles and vaccines. And

we're still inventing new ways of giving

these instructions. But all of a sudden,

medicine

is programming the behavior of cells in

a way that's much more directed than was

ever conceivable before. Like there's

really a step function in what's

imaginable and achievable in medicine.

>> Super exciting. Do you think that

molecular biology and genetic

engineering andor AI are the reasons

that things are on this accelerated

timeline?

>> Yes is the answer. All of those things

>> I think we can do experiments at a

different level of scale. we can

generate data and then we have the

computational tools in including AI but

we have computational sophistication to

actually extract insights from massive

amounts of data and you know I think

historically biology was we were it was

an observational science if you

especially if you wanted to study things

in in humans there wasn't a way to

intervene now all of a sudden we're

taking human cells we're putting taking

them into the lab and making genetic

changes is and reading out the

consequences and directly being able to

observe the effect. And we have all the

we have tools to do this with imaging.

We have the tools to do this with DNA

sequencing. And we can take this all the

way into clinical trials and see what

are the what are the consequences when

we actually go after targeted DNA

sequences and make our cells better at

treating disease.

>> Would you mind educating us about the

immune system a bit? the adaptive and

the innate immune system, some of the

major cell types, because I think those

are going to form the kind of building

blocks of our discussions about cancer

and and other things today.

>> Our immune system permeates almost every

aspect of our health and disease. It is

a system really in the sense of it it's

involved in every part of our body that

has evolved to protect us largely to

protect us against infections, viruses,

bacteria, fungus.

all sorts of foreign invasions and our

immune system has developed a balance

that is when it's working properly

doesn't recognize the cells that are

supposed to be in the body but is finely

tuned to recognize signs of things that

shouldn't be in the body and to

eliminate them. I mean at at its core

that's that's the the basic job of the

immune system

>> to recognize us versus non us.

>> Exactly.

And you you talked about the innate

versus the adaptive immune system.

Largely what we're talking about are

white blood cells. We're we're talking

about different types of white blood

cells that are either inside of tissues

or circulating in our bloodstream that

go around and play coordinated and

specialized roles in sensing when

something comes in that is not us that's

foreign that shouldn't be there.

The innate immune system does it as is

sort of thought of as the the first

alarm system that something something's

wrong. And with the innate immune

system, which consists of cells like

dendritic cells, macrofasages,

these are cells that are going around

and they're looking for patterns of

things that just generally aren't in

human cells. some signs of damage, some

signs of things that are just that

shouldn't be there in a in a generic way

in a healthy human. When those first

alarm systems get triggered, all of a

sudden these innate immune systems start

releasing things. They change their

state and they send off an alarm to

other cells in the immune system and

then they often recruit in the second

arm of the immune system that you

mentioned, the adaptive immune system.

We'll talk a lot about the adaptive

immune system today. And the major

players in the adaptive immune system

are a group of white blood cells that

are collectively known as lymphosytes.

But we'll talk about B cells and T-

cells in particular, which are major

groups of of lymphosytes. We've been

focused heavily on T- cells. TE- cells

play a central role in coordinating the

fine-tuning of the immune response. One

of the amazing things about the te-

cells is that each te- cell naturally in

our body. It's one of the few places

where each cell will actually have a

different piece of DNA that's not

inherited in in our germ line sequence.

Each tea cell will make its own receptor

that is generated largely at random

to go and sense something. And those

those sensors that get put on the

surface of tea cells are there to

engage. And if they're engaged, it's a

sign that something has has been

recognized as foreign. And so we have

this incredible diversity of of

different T- cell receptors that are

have developed on our tea cells. Each

one will have a different unique

receptor on its surface. Each cell will

have a different receptor on its

surface. And the the way to think about

these receptors is that they're sensors

for they're when they're engaged, they

send a signal to the T- cell that okay,

we found something that that you've been

programmed to recognize and program is

recognized as far and if it if the

immune system is working properly.

>> And are the genes uh that these tea

cells make as these receptors uh are

those based on experience of the of the

organism? Because you said that it

doesn't come from the germ line, but we

should clarify that the germ line is not

about infectious germs in this context.

The germline DNA is from the sperm and

egg that were your parents. It became

you. There's re combination of those

genes. And then there's you all um each

and all. Um and the tea cells are making

genes that neither your parents

necessarily expressed nor that you were

expected to express except based on what

exposure to particular pathogens. Like

why do they make certain receptors and

not others?

>> Largely random. It actually there's the

pieces of DNA at this part of the the

DNA actually recombine and get pasted

together in in unique ways.

>> So it's probabilistic.

>> It's probabilistic and that's what

allows us to have cells that lying there

in waiting for things that we've never

encountered. If a a a bacteria might

come into existence or a virus might

come into existence that doesn't even

exist now in nature, but we might have

tea cells lying there waiting that could

be engaged by those proteins on the

surface that viruses would introduce.

>> That's incredible. Would you mind

mentioning the the role of the thymus?

These days I'm hearing more and more

about we have a thymus and we lose a

thymus. Would it be beneficial if we

could keep our thymus around? So thymus

is is actually the reason the tea cells

are called te- cells is the T stands for

thymus and the thymus is an organ that

it does sort of shrink as we age but at

least in childhood it's it sort of lies

by your heart

>> and it is the place where tea cells go

in a key place of their education. So

they they've have are making these

sensors at largely at random and then in

the thymus they get cold they get

selected and they the ones that by

accident are generated that recognize

something that is supposed to be in your

body if if the T- cell engages a natural

target in the thymus those cells will

die and so what emerges from the thymus

should be and this is not perfect

process but should be things that have

are have emerged at random but then are

selected to remove things that recognize

your own body targets.

>> There's sort of a negative selection

>> of the stuff that's you so that your

immune system doesn't attack you and it

knows you from non you.

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

actually both a positive selection and a

negative selection. That's exactly the

right way to think. The cells get will

only emerge from the thymus that if they

have a a receptor on their surface

that's there. So that's one positive

selection, but if it engages with a self

target in the thymus, it gets negatively

selected. So what comes out are tea

cells that are there with sensors in

place

>> to recognize things that shouldn't be

there.

>> Okay. So your thymus and your tea cells

get educated in childhood. Yeah.

>> And that's what you're working with

>> except that the immune system can adapt

and make antibodies to things it doesn't

recognize. the antibodies come from the

from the other type of lymphosy

lymphosytes. So now now we can talk

about the B cells. B cells are this

other type of lymphosy that work in

coordination with T- cells and they're

the antibbody producing cells. So they

actually have a similar process where

they're generating different antibodies

at random through a similar kind of

recombination event. they have their own

form of selection that they go through

and then those antibodies can then be

released into the bloodstream and and

are the basis for protection against

infections after we get them. I'd like

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to get up to 27% off. What um underlies

the sort of efficiency and functioning

of the immune system? I I know I and

many people are thinking, okay, we hear

like our immune system gets activated or

our uh our immune system is impaired. Um

the one thing that I'm certain uh

supports the immune system is great

sleep,

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

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

Is that because there's a a known

impairment of the immune system?

>> I I wonder about this too. I mean, I

agree. I've experienced that so many

times of being run down and then being

being feel experiencing that I'm

susceptible to infection, but I I don't

actually know the basis of that. I mean,

it's kind of amazing how much we don't

know about these determinants of of

immune health largely because they're

often variables that are left out of the

the mouse studies that we're doing.

We're, you know, we're studying largely

steady state uh immune responses in

mice. And I I would say we don't haven't

done a full exploration yet of all the

types of ways that general health

impinges on the immune system. I had a

someone in my lab a postoc named Sager

Bapat who came to my lab with an

interest in in in

metabolic health and wanted to study the

effect of metabolic health on on tea

cells and this there's some subgrowing

stuff on this but it's another like what

what are the determinants of it

>> he did an he did experiments in my lab

where he exposed

>> some an allergen something that

irritated the skin and caused an

allergic type reaction ction in the skin

of mice. He did it in mice that were

eating a normal mouse diet versus a

highfat diet that caused obesity.

And what we saw was that it was actually

not just a qual a quantitative

difference in the immune system, but

actually a qualitative difference. The

actual type of inflammation, the cell

responses were different in in the mice

eating a highfat diet. And I think we

haven't done enough studies like that

where we actually start playing with the

variables of life and test them in in a

mechanistic way to isolate individual

variants. What was interesting there was

that the allergic reaction actually

looked totally different in the obese

mice and if we used surrogates that are

for the types of drugs that are being

used now to treat severe allergy. So we

gave antibodies that block allergic

responses. the normal lip diet mice

would respond favorably to these. It it

they didn't help the the mice that had

the obese highfat diet respon response

to inflammation and in some cases it

actually maybe made it worse.

>> So so I think that there are these these

systemic ways I mean clearly we know we

our intuition tells us this strongly

that systemic health can can feed into

our immune responses but I think it's

still been underexplored in rigorous

ways. I realize I'm asking very top

contour type questions for which there

probably aren't specific answers, but we

all know people that um get sick all the

time. Um and we know people who never

seem to catch the bugs that everyone

else seems to catch. Is there any

understanding of what a more robust

immune system is at the level? Is it

more tea cells? Is it um you know are

the the B cells engaged more quickly so

they can generate antibodies more

quickly? What is it?

>> These are great questions I I that I

don't think have full full answers.

>> There are there's been a lot of work on

genetic determinance and and there's

extreme cases where people have a

genetic gap in their immune system where

they're really

susceptible to something that healthy

people should not be susceptible to. And

you see that there are certain types of

infections that either happen or happen

with a different type of severity in

people with genetic

deficits in c in certain branches of

their immune system. And and in some

cases you can pinpoint that we just

talked about the innate immune response,

the adaptive immune response. You can

see that certain genetic mutations that

people inherit could influence one or

multiple branches of that immune

responses and the consequences that you

that manifests itself with different

types of infection. And I suspect that

there's some spectrum of that that we

see the the really you can diagnose the

really strong genetic consequences and

then there might be a long tail of more

subtle genetic that might be multi

multigenic that we don't fully

understand and then I'm sure that

there's other determinants of health

that are just multiffactorial and so

it's you know it also becomes this

interplay between the health and then

what you get exposed to by by your

environment.

>> Yeah. Speaking of which, I'm familiar

with some studies from Stanford, I

believe, where um kids that have no

exposure to peanuts get peanut allergies

and um careful subtle

>> increasing exposure to peanuts

essentially um protects them against

peanut allergies. So, is it true that

when we're young that exposure to

pathogens um and different foods uh

gives us a more robust immune system? I

think that there's the what we're

exposed to and what we develop tolerance

for is is critically important during

there's some windows of early life that

I think are we're particularly

susceptible to becoming tolerant

>> and I think if we don't get the proper

exposure to certain things all of a

sudden our our body can start to be

hyper sensitive to them which manifests

as allergies now there's this balancing

act I think the fear of allergies makes

people more more hesitant to expose kids

and I think you can it can get into

these these dangerous zones of you don't

want to expose kids who are going to

have a a dangerous allergic response but

on the other hand critical early

exposure is part of how tolerance is

maintained and I I think peanut

allergies there there is strong evidence

that exposure to peanuts can be

beneficial

in people who are not yet allergic

>> what's going on with autoimmune

conditions

>> is this that the the B cells and T-

cells are at probabilistic level that

tea cells developed um some reaction so

to speak a binding to um cells that we

naturally make that they shouldn't have.

It's just like it happens.

>> I've always been intrigued by by the

idea that when the immune system is

really ramped up

>> um people will experience autoimmune

like symptoms. I had experienced that as

a master's student. I I was working so

much

>> and probably not eating enough and

drinking so much caffeine back then that

I got some kind of funky skin lesion

things. I went to the doctor and like,

"Oh, you're starting to get some attack

of the deeper layers of of your skin.

Um, you just need to work a little

less." And sure enough, did that trick?

>> It did the trick, you know. But I I was

just it made me so keenly aware of how

um the immune system will for lack of a

better word adapt to conditions and it

was trying to keep me healthy and it it

overshot the mark basically.

>> I sort of walked you through at a first

principle like how things are supposed

to work. I told you okay there's this

process of generating receptors on the

surface of T- cells. Antibodies get

generated on B cells. They go through

this positive selection and negative

selection. That's a delicate balancing

act and it doesn't actually work that

way in practice. In in practice, TE-C

cells escape from the thymus that do

recognize our own self antigens and

there's actually secondary mechanisms

there to block that. But autoimmune

diseases emerge when those normal checks

fail.

>> This and I think it's a consequence that

the immune system has two major

responsibilities. It has to be primed to

protect us from infections which would

be fatal and be strong and recognize

this incredible diversity of potential

foreign dangerous things that we might

experience. But it also has to not

recognize our own cells. And it can miss

the mark in both ways. And so autoimmune

disease manifests in different tissues.

If if you if your immune system starts

recognizing targets in your joints, it

can cause rheumatoid arthritis. If it's

in the cells that produce insulin in the

pancreas, it causes type 1 or childhood

diabetes. Um, if it's the my mileinated

cells in the brain, it's multiple

sclerosis. So, this is autoimmunity and

inflammation of different kinds cause

their own pathology. So, we want to the

immune system is always these sort of

two sides of the coin. Making sure that

we're having strong responses to

infection.

We'll talk about cancer where we want to

also strengthen our responses. But for

autoimmunity, inflammation, allergies,

we want to make sure that like our goal

therapeutically in with drugs is to make

sure that we make the immune system

under control

and ideally do it in a targeted way so

that you don't have to turn off the

whole immune system with blanket

immunosuppression, but to do it in a way

that just makes you tolerant or not

reactive against the things that are

being inappropriately targeted by the

immune system.

Two things that I'd love to understand

about the immune system is uh how is it

that um an immune response let's say to

a cold virus is systemic like like where

is the sort of master uh uh controller

is it or maybe it's a distributed system

that says like okay we need to launch a

a bodywide response as opposed to a

localized response. I can I can imagine

like with a splinter, of course, you're

going to get a localized response.

>> It's a little piece of wood or metal and

so you're going to get the innate

response and you're going to get some

pus around it and it'll kind of localize

the wound. But

>> when it comes to an invasive virus like

the cold virus, uh it overtakes us,

right? The production of mucus, we got

the headache, like the and I think it's

the systemic effect that um that

intrigues me so much. like where is the

signal to to to launch a systemic versus

a localized response in the immune

system? How does it determine that? You

know, I think some of it depends on on

what virus we're talking about, how

systemically invasive the the different

viruses can be, and some of it can be

that the immune system has different

levels of, you know, it can have a local

response, but the immune system, the

cells that we talked about in the immune

system, one of their jobs can actually

be to secrete things into the

bloodstream, things that are essentially

chemical signals that something is

wrong. major ones are they're called

cytoines and they can act locally but

they can also have more distributed

effects and some of the things that that

that the cytoines can do can influence

what can cause the development of fever

right so you you can have these sort of

cascading effects of something being

recognized at a particular site in the

body then sending distributed signals to

the blood that will make us feel sick

and you know in some cases there's again

this balancing act of maybe a fever

gives us some edge in fighting s some

some types infection, but it also makes

us feel lousy. And so the you know the

the immune system is is always walking

that I think in sometimes the immune

system immune system response to

infections is too strong and a lot of

the the negative consequence of what we

experience is the immune system going

too far and having to come back as as

the as the as an infection gets under

control.

>> Thank you. One of the reasons I asked

that is well I hate being sick.

Fortunately I don't get sick too often

if I take good care which I think is

like most people. I think about

antibiotics for instance. Antibiotics

are amazing.

>> Yeah.

>> I've had a few things where I was like,

"Ah, this thing's bothering me." And uh

like I had this sinus infection a few

years back and I was like, "Ah, this is

definitely not a cold." And then they

tell you it's not a sinus infection

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

Now, I'm not a physician of course, but

um it got really bad.

And I took antibiotics and within a day

I was feeling substantially better.

That's great. Many people have such

experiences with antibiotics. I realize

they can be overprescribed and you can

end up with antibiotic resistant

infections. That's a concern for sure.

But what is the sort of inherent danger

of using things like antibiotics the way

I described like not in a in a life or

death situation to mitigate the duration

or the intensity of some sort of

infection because surely you're

shortcircuiting your immune system's uh

ability to eventually just fight that

thing off. Like is part of building a

robust immune system across your

lifespan, allowing your immune system to

do the work and going through the misery

of being really sick and infected?

>> I don't think so.

>> Great. Okay. Fantastic. Love that

answer. Love that answer.

>> I think you probably were exposed and

had an immune response. Antibiotics when

they're used for bacterial infections

that that are susceptible to them are a

miracle. And you know, we live in this

amazing sliver of human history where we

have antibiotics that can cure disease.

I mean, I think many of us have had

bacterial infections of different kinds,

cuts and wounds that would have been

deadly in other generations. And we're

we're we're the beneficiaries of having

antibiotics that work. We are at some

risk that if we overuse them, that

window of human history might come to an

end if we don't continue to replenish

new antibiotics. But we gain more and

more bacteria that are resistant to

antibiotics.

>> Are people developing new antibiotics?

>> It's an underfunded area of medicine

>> because I just hear a moxicil pen. I

have a friend over in the UK who's been

having some some eye symptoms that

>> um from what I'm learning, we're still

learning is likely an infection uh in

near the posterior chamber, which just

simply means his vision is potentially

at risk. Systemic antibiotics are very

likely going to save his vision. And so

people say, well, antibiotics are bad.

Like a hundred years ago, we probably

would have just they would have just

inucleated the eye, which is be blind,

right? So it's I think they're a

spectacularly good tool, but it seems

like there's just a kit of maybe what a

a five to a dozen very commonly

prescribed ones. Why aren't people

developing better, newer, new generation

antibiotics? Seems like it would be a if

for no other reason, a trillion dollar

industry, but also save a lot of lives.

I don't know whether there's a business

reason for that or it's but it is an

underfunded area like it's it's not

where medicine has has turned enough

attention and I I do think it's a

genuine risk.

>> All right. Well, some entrepreneurial

young uh guy or gal or both will will

launch into it.

>> Um

>> I want to understand the relationship

between the immune system and cancer.

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

like people say oh you know cancer is a

new thing because of the advent of you

know all these devices with EMFs and

radiation. That's certainly not what I

believe. Has cancer been around a very

very long time. Do we have evidence for

that?

>> Yeah. Yeah. I mean if anyone's really

interested I I would highly recommend

this book the emperor of all maladies

which is a which is really a biography

of cancer as a disease and talk about I

mean the long history of going back as

far as there's records of tumors of

various kinds and and the misery

associated with that we have a very

different understanding of of cancer

right now right and I think cancer is

one of the most sophisticated where we

have one of the most sophisticated

genetic understandings of disease

doesn't mean we can always do things

about it but now we can understand

mutations that accumulate in in cells

and all of a sudden so the DNA inside of

a healthy cell is there programming so

if you have a skin cell your DNA is

programming your skin cell to be a a

skin cell in cancer all of a sudden some

combination of mutations emerge in that

cell that

lose its normal regulation it the skin

cell is no longer getting the proper

signals from its DNA to stay in the

right place and it goes and switches

into a mode where it's dividing out of

control and the result is that those

cells will then transform into cancer

cells. They'll start dividing. They'll

lose the normal architecture. The risk

is that they can disrupt things in the

in the tissue where they are or that

further mutations can accumulate and

they can actually start spreading into

distant sites in the body and that's

metastasis. When you when you're when a

cancer goes from one local site to

another part of the body and as that

happens it the those cancerous cells

it's it's really an evolutionary process

where those cancerous cells have

acquired new genetics that are focused

on their well-being. Those cells are

dividing. They're growing out of control

and they're taking the resources.

They're they're they're growing at the

expense of the normal coordination of

the human body. And and that's that's

really at at its core what what cancer

is. It's genetic disease where cells

lose the normal pro uh regulation and

are dividing out of control in various

tissues.

>> I can see the picture in my mind where a

otherwise healthy cell gets a mutation.

We can talk about how mutations arise

but and then starts uh spitting off

daughter cells as it's referred to.

>> Yep. Why would the daughter cells

inherit the mutation necessarily to then

create more cells because that's the

prol proliferation of the tumor?

>> Yeah,

>> certainly cells propagate their DNA into

their daughter cells. But um

I could imagine a situation where every

day some of our cells get a mutation,

spit off a couple daughter cells, and

then those daughter cells are are

terminal as we say, right? And they

don't create more cells. Is that

happening all over the body every day?

So does this so how is it that a the DNA

that creates the further propagation

gets passed from one one cell to the

next? I do think this is happening

constantly. It's a process that every

time a cell is around especially as it's

dividing there is some imperfection in

how the DNA the DNA has inside each of

our cells if that cell is going to

replicate the DNA has to replicate

itself. So you end up with two copies of

DNA that should be the same. Each one

being passed on to the two daughter

cells of that dividing cell.

That process of DNA replication is

imperfect. And if there's any kind of

damage during that process, one of those

two copies might end up different than

the other one, in which case you end up

with a mutation now in one daughter cell

and not the other.

If that is dilitterious or if it's

damaging, which probably most mutations

are, those cells might start to die off.

Okay. Something got the DNA got messed

up. Those cells that are carrying that

DNA die.

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

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

>> And there's a lot of control mechanisms

in the cell that say something

something's wrong. Let's send a a

programmed cell death signal to that

cell. And cells will kind of implode

with with various processes when

something's wrong. And that that happens

most of the time. The problem is if if

if that change all of a sudden starts to

not be damaging but to actually be a

signal. Okay, now the cell is is growing

more. It has some benefit that it's

accumulated as a result of that

mutation. Now that cell will start to

divide more

>> and that that cell that's carrying that

first mutation might start dividing

more. It both of its daughters now will

pass on this this mutation that's made

it divide more. And if in subsequent

rounds it gets a second hit, it that the

combination may go from just cells that

are dividing a little bit more to cells

that take off and become full-blown

cancer. Now, there's certain processes

that will accelerate that.

>> One was exposure to things that cause

DNA damage, right? The major one is is

smoking. When smoking causes chemicals

to go into your lungs, the the lung

cells get exposed to these chemicals

that then cause higher amounts of DNA

damage, more mutations, and just as you

have more mutations at a higher

frequency, you're more likely to

accumulate the set a set of mutations

that will gradually go on to cause the

generation of cancer. Another way that

is that this process can be accelerated

is that some people carry an underlying

genetic predisposition to cancer. So

people you will likely have heard of the

brocha or the BRCA genes which

predispose to breast cancer and other

types of cancer. There people start with

one copy that's already setting them on

a road to higher risk of mutations

accumulating and the whole process on in

happens with a higher frequency and so

this this march towards cancer cells is

more likely to occur in people with that

type of predisposition. How common is

the BA mutation? Uh is it equally

distributed in men and women? Um yeah,

what can you tell us? And should

everyone get tested for BA? And there's

a lot of questions here. I'll ask them

again one by one. Um and then of course

we'll talk about things that could be

protective, not just but certainly

avoiding smoking would be paramount. So

how common is

>> breath? Yeah. So in terms of mut

mutagens like the big ones are smoking

>> sun exposure for melanoma. You know I

know the balancing features of sun

exposure but

>> yeah we can talk about that

>> but but clearly UV is is a risk factor

for

DNA damage in the skin.

>> I mean I'm perfectly happy going on

record. My the things I've said around

in sunlight have been contorted so many

different ways. It's like a pretzel

twist now. No it's more like one of

those balloon animals at a party but

it's not it's a mess. The too much UV is

bad for for skin cells. It's just bad.

You need some, but too much is bad. Long

wavelength light is great uh for and

therein lies the challenge. But yeah,

love sunlight, but you don't want

excessive UV. Don't get avoid getting

sunburned, folks. Yeah, thank you.

>> So, yeah, the BA mutation. And I have a

personal relationship to this cuz I lost

both my graduate adviser and my

post-docctoral adviser to bracka

mutation related cancers 50 and you know

just a little bit older than 60 and the

other and you know brutal um especially

when you you know one of them I know

they're kids and you know it's um just

for young people getting cancer and I

know they're childhood cancers but

ba seems pretty common.

>> I don't know the numbers off the top of

my head. I mean they're not the major

like numerical causes of of of cancer in

the scheme of cancers that developed.

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

relatively small set number of the full

set of cancers. The problem is if you

inherit a broco mutation as an

individual you have a very high risk of

developing cancer. So it as an

individual your risk goes way way up and

of certain types of cancer in particular

>> and we can all get tested for it now

pretty cheaply right.

>> Yes.

>> Yeah.

>> Yeah. That's certainly recommended if

there's a family history of of cancer

for broa mutations and a a couple of

other ones. But you're right it's the

tests are available. And you asked about

men and women. Mhm.

>> It actually was was men were were some

of the ways that those broco genes were

identified because it's so rare for men

to develop breast cancer. The ones who

did develop it there was a thought well

maybe there's an underlying genetic

predisposition and that helped identify

those genes.

>> Interesting. Um everyone get tested for

broa if you know because there are

lifestyle factors that can reduce your

cancer risk. I'd like to talk about

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

on record saying vaping bad. Perhaps not

as bad as smoking, but still way way

worse than not vaping. Uh, the battle to

sort of protect vaping is is like beyond

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

own. Um,

environmental sort of and workplace

hazards, you know, like known mutagens.

If you work in a laboratory, you're

working with mutagens, right? You're

working with things that literally pull

DNA apart. Yes. This always worried me

working in a laboratory. There are a lot

of carcinogenic chemicals in a

laboratory

>> for good reason. Yeah. This is the Yeah,

we're we're trying to study cancer, but

we're certainly working around a lot of

things that could cause cancer,

chemicals,

>> radiation.

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

I did a lot of lot of experiments radio

lababeling cells.

>> Yeah. I mean we well fortunately we

worked with

uh you know radiotagged amino acids with

radiation that was we were told and I do

believe was not not as as dangerous as

some of the others but yeah I mean so

chemical exposures are a big one. Yep.

>> And so those those labels on paints and

thinners and stuff in the garage that's

real that's a real thing. They mutate

cells

>> and there's a you know there's some

spectrum of stronger and less strong

ones. And I think oftenimes we're

operating in an absence of great data,

but I you know I think there's a lot of

things are implicated as potential

mutagens,

>> pesticides. Yeah, I

>> you look at cancer rates in in um rural

areas near where you know crops are

dusted with pesticides and we've had

Shauna Swan came on here and she's like

listen you know the the cancer risks the

you know endocrine disruptor risks we

think of as like big cities as as dirty

and dangerous and they are for certain

reasons but she said if you really see

the spikes in uh in these cancers uh

related to environmental factors it's

less so bus exhaust than it is

pesticides.

>> I mean, it is not evenly or fairly

distributed. Some people get exposed way

more to these things and we haven't

studied them enough. We we need way more

study to really be able to answer. Okay.

And and and people shouldn't be left,

this is my just me just speaking as it's

kind of amazing to me how much we're

left on our own to be figuring out what

the risk of individual products is. And

I I think it's a place where we should

be investing a lot more to get clarity

on where the real risks are.

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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

prefer to do the slower um manual pat

down at the airport um to going through

the scanner. It's a low level of

radiation

>> is what they tell me. But if you're

traveling a lot, you're getting multiple

low-level exposures. And we know pilots,

and this is for other reasons because

they're, you know, you can tell us, but

atmospherically they're exposed to more

radiation. Cancer rates are higher in

pilots. Now they're sitting a lot too.

Prostate kids. Okay. There's a bunch of

things there, but um do you yourself

avoid the scanner at the airport?

>> Honestly, I I do, but I can't say that

there's data for that. I I feel the same

way as you. Like if I could avoid it, I

I try to minimize,

>> but I that's not based on some inside

knowledge I have, but I have the same

>> bias of less seems better.

>> Yeah. I mean, I'm not out to get the the

scanner industry. Yeah, just I think

it's useful for people to hear that that

you could that one can have no formal

data but an understanding of mechanism

that leads them to

>> to hedge.

>> 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

it's those mutations may or may not be

linked to to cancer, but by virtue of

the fact that you're causing more

mutations, almost inevitably you're also

increasing the risk of cancer and

carcinogens are things that increase the

ris rate of cancer.

>> I love barbecued meat. I don't like

barbecue sauce because it's sweet, but I

I like meat with a char.

>> Yeah. Yeah.

>> Is the char bad?

>> I think so. I mean, I like it, too, but

Yeah. Yeah. Again, these are balancing

decisions in life. Sure. But yes, there

there there's some there is I mean meat

in general has been implicated as a

potential carcinogen, especially in

colorectile cancer. There's some data

around that.

>> Mhm. Yeah. My read of those data, not

the char data, but the the me data is

it's tricky. Um

>> from my this is just my standpoint. And

I want to make sure I'm I put you know

brackets around this that this is my

read of the literature is that many of

the studies that looked at

>> meat rich red meat rich diets versus uh

plant-based diets. The problem is a lot

times the red meatenrich diets had a

bunch of other things in them like

sourcing wasn't considered. There was

also a lot of um starches like because

nowadays you find people who seem to at

least feel better. Who knows about the

longevity aspect, but feel better eating

red meat, fruits, and vegetables,

limited amounts of starches versus so I

feel like the nutrition studies are a

mess. They're kind of a disaster.

>> I I certainly don't have clarity on

that. Yeah. Yeah. And they and it seems

like it changes the the the direction. I

think some things we have pretty good

common sense intuition about

>> fiber.

>> Yeah. ultrarocessed foods are probably

bad like you know but I I think the

balance of exactly what whole foods

we're eating probably still needs to be

worked out.

>> How do you think about the data um on

like for instance food dyes this is very

timely um where a certain food dye yeah

>> at a very very very high concentration

in laboratory animals creates a

significantly higher

>> incidence of of tumors and cancers in

those animals. But then the amount of

food dye that's in the human food is is

is a tiny fraction of that. Um I'm not

trying to get political here. I just

think as a framework for people to think

about

>> there are many carcinogens I'm sure

right in this environment. I don't doubt

that the lacquer on this table in fact

if that's even what they used um uh if

ingested could cause um could cause

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

Right. But I don't know that in its in

its form here being near it uh for many

hours a day does that. I I doubt it.

We're not inhaling the table.

>> This is what I mean by this this this

level of confusion. I think we all live

with this background confusion of things

some study has been published in in mice

at whole high concentrations exposure

does mean anything in our lives. What's

the relative risk? So that's why I start

with smoking sunlight and then say

there's a tail. And I I don't think we

know fully what that distribution is

yet. I'm sure there are some combination

of things that are increasing our risk

of cancer. We don't really know how to

weigh uh duration and amount of

exposure. And this is why I think it's

really scary to people. People don't

know, you know, they know smokers who

don't get lung cancer

>> and non-smokers who do

>> and non-smokers who do. And so I think

people go well like what they it

actually has caused I I believe a lot of

um damage in the faith in in medicine

unfortunately because the messaging is

all uh is mixed up.

>> Yeah. I think that nowadays people are

trying to do what they can to protect

themselves, but people still get cancer.

You can do everything right and still

get cancer. Is that

>> even if you don't have a bracket

mutation?

>> Absolutely. I mean, absolutely. You

know, I think the last thing you ever

want to do is like attribute someone's

actions to to cancer. I mean, it is it

is a probabilistic disease where some

set of mutations occur that cause a

really devastating disease. And so I

yeah I mean I we don't know the answers

and I think we have to be humble about

that. Now what I I think we can also

talk about is well like how how do we

handle how do we treat cancer when it

comes up and this is where these two

conversations that we've been having

really come together of when talking

about the immune system. We went through

a lot of I think I mean actually we went

through a lot of sort of detailed

mechanism thinking about the different

cell constituents of our immune system.

I will tell you that when I went to

medical school, which wasn't that long

ago, I graduated in 2010,

the dogma was don't waste time thinking

about cancer immunology.

Cancer immunology is a field that's

going nowhere.

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

think that was a maybe there was some

local bias in that direction, but this

was not the mainstream of thinking about

how we would treat cancer

>> at that point. that the way the cancer

was being treated was chemotherapy,

which you know is something that's been

around for decades. And it's basically

give toxins to the body that will be

more toxic to the cancer cells than to

the healthy cells. And ask people to

endure all the side effects because they

have to to get rid of the cancer cells.

And that's still the mainstay of of of

cancer treatment. We all want to do

better than that.

>> It's very unpleasant. Very very

unpleasant.

>> Unpleasant and and worse. I mean I mean

people endure hor you know it's it's we

put put we put people through horrific

things because it's the best we can do

>> and then there was a wave of thinking

okay well let's try to make drugs that

are targeted to the mutations that we

talked about and that was that was the

hot thing that was the promising avenue

when I was in medical school of like

okay now we we've really measured that

these are mutations that accumulate

inside of cancer cells this is what's

causing cancer let's let's make drugs

that go after those things And turned

out that that was although a lot of good

has come from that people have extended

lives, cancer has a way of working

around that. And

>> so these are cell cycle inhibitors.

>> So signaling thing various mutations

affect this these growth properties of

of cells and there's targeted drugs that

have been designed to go after some of

those pathways that are making the cells

divide out of control. Yeah, I think

that benefit has come but cancer has

ways of mutating around that and become

developing resistance. The same way we

talked about resistance in bacteria to

antibiotics if they're exposed you can

cancer cells are can evolve quickly and

can become resistant to these targeted

modifications.

What has emerged as a whole new way of

thinking about going after cancer is

using the power of the immune system

that we talked about at the beginning

and redirecting that against cancer

targets.

This has changed how we think about

cancer treatment. It's the hope is that

all of we tal we we talked all of us

have this immune system that goes

through every organ in our body. It

circulates. We have white blood cells

that are constantly going around and

looking for things that shouldn't be

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

where there are drugs that get infused

that hit these things that are on the

surface of TE-C cells and they actually

are natural breaks to the TE- cells.

Te-E cells might be in our body there

but turned off or not turned on enough

to be strong enough against cancer. And

for certain types of cancer, it's been

absolutely miraculous that if you make a

drug that hits the break on the on the

tea cells, the tea cells go stronger and

they can be unleashed against cancer

just by taking the brakes off of them.

>> What sorts of cancers has it been

successful for?

>> The poster child for this has been

melanoma. Mhm.

>> One of the big success cases was was

Jimmy Carter who had a melanoma which is

a skin cell aggressive skin cancer that

had already gone to his brain which was

thought of as a death sentence and he

got treated with checkpoint inhibitors

and basically was cured.

>> Amazing.

>> Um and so you know they saw these tumors

just shrink away and in and not just him

but in a in a large fraction of of

melanoma patients now respond to these.

And so that that has changed how

melanoma is treated. It's and other

cancers to varying degrees because some

types of cancers can respond to this.

That's taking the a drug that unleashes

the tea cells that are already in our

body. The focus of my research in is

well

the first thing I said was we're living

in this amazing moment of biology where

we can we can do things to cells in our

body that with incredible precision and

and we're often just limited by our

imagination. And what we can see now is

that we don't actually have to just be

limited to the cells that the tea cells

that are natural in our body that

already have this random distribution of

sensors. We can actually genetically

make a a one of these sensors for tea

cells and put it into te- cells. We can

put in put a gene that encodes something

on the surface of tea cells that will

make them programmed to search and

destroy for cancer cells.

>> Now, this is this is largely known as

chimeriic antigen receptor tea cells.

That's a long term. They're known for

short as CART cells, chimeriic antigen

receptor. And what that means chimeic is

that these are stitched together. This

is a receptor that was designed in a

lab, does not exist in nature, but can

be put into a piece of DNA, delivered

into a TE-C cell, and when that DNA goes

into the genetic code of the T- cell,

all of a sudden the T- cell will start

making proteins that go on its surface

and act as these artificial sensors. And

those cars then when those tea cells get

reinfused into a patient the way that

you get like a a blood transfusion

those cars are directed to go against

cancers. This has been done for certain

types of leukemia and lymphoma. And

there's been these amazing success

stories. The thing that woke up me and

the world was in 2012

there was a young girl who was the first

pediatric patient to be treated with a

cartis cell for for cancer. So she she's

become a heroic figure uh Emily

Whitehead. She was I think eight at the

time and she had a form of leukemia that

hadn't resp it just was for some reason

whatever reason it failed all the

treatments and it just nothing worked.

She was going to be sent home on

hospice. She had exhausted all the

possibilities at the age of eight and

she got enrolled in a at that time

highly experimental treatment to get

these CAT tea cells. So her blood cells

were taken out in a big blood donation.

her own tea cells were genetically

modified and we could talk about how

that was done. It's actually done with

like a pretty crude technique that's

been around actually used viruses,

lentiviruses. These are sort of modified

HIV viruses to deliver this extra piece

of DNA that encoded the car. And this

was done on her cells. And then after

that extra gene was put into the tea

cells, the tea cells were reinfused into

her body. And it was not a

straightforward course. She she ended up

in the ICU. The immune system had to we

people in real time people had to figure

out how to control the immune systems

and the side effects. But as that was

controlled, all of a sudden the her

cancer cells disappeared.

>> Amazing. And the lentivirus itself

didn't uh didn't spark a an immune

reaction that was

>> that outweighed the benefits of of the

cargo.

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

there there's been some discussion about

the risks of using these lentiviruses

and we we'll talk in a second about how

we can do better now.

>> Yeah. People are going to hear uh

putting viruses into cells and putting

them into humans and a bunch of people

will freak out. But I I promise you that

things like adeno, which is like a cold

virus, or lenti, which is similar to

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

HIV. They changed the virus, so they're

not delivering HIV. These viruses are

incredible because they can create

longlasting expression of genes that you

deliberately put into them. They're a

shuttle.

>> It's an amazing application of

biological understanding, right? that

all of a sudden we've been studying

viruses because of the risk that they

have, but we've learned that they can

deliver that that viruses have evolved

to be very good shuttles

>> and to deliver their genetic material

into cells.

>> The way I think of it uh that is the

viruses have evolved to take advantage

of our biology and our genes. And so we

did the ultimate touch in these

instances like you're so good at at

hijacking our cell's DNA and

proliferating. All right, we'll leverage

you to help us as opposed to hurt us.

Right.

>> That's exactly right.

>> And so that was done in 2012. Emily

Whitehead was eight.

It was done as an experimental treatment

at the University of Pennsylvania. And

the story now is that now all these

years later, Emily White is not only

cured of her leukemia, she's premed at

the University of Pennsylvania.

>> So awesome.

>> And so no one could ignore that. You

know, this was this wasn't this was just

all of a sudden this dogma that I had

just been taught a couple of years early

in medical school that we should ignore

cancer amunotherapy. It was just we were

just wrong.

>> And all of a sudden the field woke up

and said, "Okay, the immune system is

not just limited to treating viruses and

bacting us from viruses and bacteria.

The immune system can be exploited and

potentially re-engineered to protect us

from cancer and maybe other diseases."

So that was 2012.

2012 also was the year that a paper got

published in science by Emanuel

Sharpantier and Jennifer Dana that

introduced this new technology called

crisper

and we can we'll talk about this but

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

itself cloaked from the immune system,

now with crisper, we can think about

getting one step ahead and making tea

cells that are able to be resist all the

tricks that cancers throw at it to be

more and the I think we're on the brink

of having precise crisper engineered

cells that will I I hope start to melt

away cancers without the side effects of

chemotherapy.

>> Amazing. Uh just amazing. And the story

of this young woman is spectacular. Um,

>> I have two questions before we talk

about crisper technology. The first one

is, is it true, I believe it is, but is

it true that cancer risk goes up as we

get older?

>> And if so, why? Um,

so that's the first question. And then

uh the other question has to do with how

the the amunotherapy that you described

um was able to target the cancer and and

not cause problems elsewhere which is

kind of the major issue of chemo and

radiation therapy. But the first

question um again was you know why more

um mutations as we get older. So I think

there's there's a few cancers that that

peak in childhood and there's risk as as

the body's developing of certain cancer

childhood cancers and there's childhood

leukemas for example then that like when

we talk about Emily Whitehead but most

cancers as you said exactly as you said

that there's this sort of increase and

they're largely disease of later stages

of life. I think that the reason for

that is remember when we talked about

what causes cancer it's this evolution

where c cells start to accumulate

mutations numerically a lot of the cells

that have the mutations will die off and

it's just a game that unfolds over time

and the more time you have cells

dividing and sticking around in the body

they're accumulating more damage and

eventually you're more likely that that

damage would actually transform the

cells into a cancer cell. So time is is

is is a big factor here. time and just

accumulated damage.

>> And the other question was, you know,

how is it that the lentivirus knows to

um the lentiviral

uh cargo carrying tea cells uh know to

attack the cancer and not something

else.

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

right?

And I think one of the things that

worked incredibly well was a brilliant

choice by a group of scientists in

different a few different places that

converged on the target that was used in

the first CARTT cell. And what the

target is known as as is is a protein

called CD19.

>> That's just the name of this thing

that's found on a lot of different types

of B cells. So this brings us back to

this discussion. the the leukemas

themselves are a disease, a cancer of

the immune cells. So they're cancer of B

cells and CD19 is is found on the on the

surface of many a large number of

different types of B cell leukemas and

lymphas.

>> I see.

>> I think one of the things that turns out

to be serendipitous here is that B cells

themselves natural healthy B cells

actually also have CD19 on their

surface. What just turns out to be

serendipitous is that the body can

tolerate those cells going away. And so

what has made this a particularly

effective and safe and relatively well

tolerated treatment for cancer is that

the collateral damage is actually not

that damaging. That te- cells in this

case are not strictly distinguishing

between cancer and health. They're not

just getting the leukemia cells. They're

they are getting collateral B cells. But

by and large to a first approximation,

people can live without those cells. And

so that side effect has just been

tolerable.

Finding that balance gets harder and

harder for more cancers. Right? If you

start to think about pancreatic cancer

or brain cancer, finding targets that if

you hit the healthy pancreas or the

healthy brain are not toxic, it's it's

harder and harder. So people are

thinking about more and more

sophisticated ways to look for these

targets that are selectively found on

the cancer cell and not on the healthy

cell or to think about ways that you

might actually make the cell depend on

recognizing multiple features so that

you can have what's sometimes talked

about as like a two-factor

authentication like the T- cell will

only kill cancer if it finds this and

this and that combination of things are

not found on healthy cells even if one

or the other might be. So people are

thinking about how do we

>> get more sophisticated about building

these discrimination systems into tea

cells. The building blocks are there but

the specifics for each cancer have to be

invented but but we have the tools to do

that.

>> Awesome. Before we talk about crisper

there was one other question that I know

many people will be thinking about. Uh a

few years back, maybe five, ten years

back, there was a a lot of discussion,

maybe even some enthusiasm about

ketogenic diets to treat or prevent

cancer. And my understanding from

looking at that literature was that for

some cancers it perhaps, I want to bold

uh underline and and capitalize perhaps

um might help, but for other cancers it

could make things worse. And then uh I

also more recently started hearing about

uh low glutamine diets. Um so and of

course this is the way the internet

works but um but I did see some papers

in some decent journals you know uh that

at least we're exploring this. So are um

low they're just low carb let's call it

what they are ketogenic diets um have

they been shown to be useful for

treatment or avoidance of cancer?

>> I have to defer to you. I actually I

don't I don't know the answer to that.

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, 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

Crisper is actually also a story about

uh how science works

>> and that's important too.

>> I think it's exactly true. I think it is

a perfect illustration of something

where a discovery happened that no one

was planning

>> but changed biology. Um

let me tell this story in two separate

arcs. One arc is the arc of

understanding DNA. You know, if you go

back to Watson and Crick, it's

understanding the double helix to

understand the structure of the DN what

a DNA sequence is that mature as we

learn how to sequence to understand the

to be able to measure a row of ATS and

C's and G's that in whatever combination

they are will start to be the building

blocks for programming which proteins

get made inside a cell. And then around

2000, we get to the first draft of the

human genome, which is this

multi-billion dollar project across the

world to come up with a draft of one

human genome sequence

milestone for for biology and medicine.

And then DNA sequencing technologies

continue to improve and cost comes down.

We're getting to the point where we can

start to measure big chunks of our DNA

at increasingly affordable costs. And

people were starting to understand the

differences between people with DNA at

the level of at least statistics. Okay,

people with this disease are more likely

to have this this gene than that. But

we're getting to some limit of what we

can do just by sequencing DNA. All of a

sudden, you you're observing the DNA

sequence that's in someone's cells, but

you don't really know what those effects

are. Just as the sequencing world is is

maturing,

we're desperately looking for a tool to

say, well, now we want to as we have all

the sequences, we want to be able to see

what happens if you change a sequence.

And people were stumbling around looking

for

different tools. There were there were

there was a range of these things. There

were zinc fingers. that people

lentivirus was another one that we just

talked about that with different degrees

of efficiency and people were trying to

to be able to change DNA sequences and

cells and it had been a long-standing

effort.

Out of nowhere emerges crisper as the

answer to this problem. crisper was

being studied as an an

interesting and unusual set of DNA

sequences that were found in certain

types of bacteria.

There were these repeated sequences and

no one knew what they were. And people

out of real basic curiosity about what

was happening in bacteria started

studying these repeat sequences and what

they were doing. And little by little by

little it was worked out that these

repeat repeat sequences actually ba

formed the basis of a kind of immune

system for bacteria.

>> Now we talked about the human immune

system. Bacteria are just an individual

cell but they're also susceptible to

infections which is a sort of a strange

idea. Bacteria cause infections in us

but there's this arms race between