Experiments that point to a new understanding of cancer Mina Bissell

now I don’t usually like cartoons I

don’t think many of them are funny I

think find them weird but I love this

cartoon from The New Yorker so the guy

is telling the cat don’t you dare think

outside the box well I’m afraid I used

to be the cat I always wanted to be

outside the box and his portly because I

came to this field from a different

background chemist and a bacterial

geneticist so what people were saying to

me about the cause of cancer sources of

cancer all for that matter why you are

who you are didn’t make sense so let me

quickly try and tell you why I taught

that and how I went about it so to begin

with however I have to give you a very

very quick lesson in developmental

biology with apologies to those of you

who know some biology so when your mum

and dad met there is a fertilized egg

that round thing with that little blip

it grows and then it grows and then it

makes this handsome man so this guy with

all the cells in his body all have the

same genetic information so how did his

nose become his nose his elbow his elbow

and why doesn’t he get up one morning

and have his nose turn into his foot it

could it has the genetic information you

all remember dolly it came from a single

memory south so why doesn’t it do it so

have a guess of how many cells he has in

his body somewhere between 10 trillion

to 70 trillion cells in his body

trillion now how did these cells all be

the same genetic match

y’all made all those tissues and so the

question I raised before becomes even

more interesting if you taught about the

enormity of this in every one of your

bodies now the dominant cancer theory

would say that there is a single

oncogene in a single cancer cell and it

would make you a cancer victim well this

did not make sense to me do you even

know how a trillion looks now let’s look

at it there it comes these zeros after

zeros after zeros now if point 0 0 0 1

of this South got mutated and point 0 0

0 0 1 got canceled you’ll be a lump of

cancer you’ll have cancer all over you

and you’re not why not so I decided over

the years because of a series of

experiment that this is because of

context and architecture and let me

quickly tell you some crucial experiment

I was able to actually show this to

begin with I came to work with this

virus that causes that ugly tumor in the

chicken rouse discovered this in 1911 it

was the first cancer virus discovered

and when i call it oncogene meaning

cancer gene so he made a filtrate he

took this filter which was liquid after

he passed the tumor through a filter and

he injected it to another chicken and he

got another tumor so scientists were

very excited and they said the single

oncogene can do it all you need is a

single oncogene so they’d put the cells

in culture chicken cells dump the virus

on it and it would pile up and they

would say this is malignant and this is

normal and again this didn’t make sense

to me so for various reasons we took

this oncogene attached it to a blue

marker and the injected it into the

embryos now look at that there is that

Butte

tiful feather in the embryo every one of

those blue cells are a cancer gene

inside a cancer cell and they’re part of

the feather so when we dissociated the

feather and put it in a dish we got

massive blue cells so in the chicken you

get a tumor in the embryo you don’t you

dissociate you put it in a dish you get

another tumor what does that mean that

means that micro environment and the

context which surround ourselves

actually are telling the cancer gene and

the cancer cell what to do now let’s

take a normal example the normal example

let’s take the human mammary gland I

work on breast cancer so here is a

lovely human breast and many of you know

how it looks except that inside that

breast there are all these pretty

developing tree-like structures so we

decided that what we like to do is to

take just a bit of that mammary gland

which is called an asanas were there are

all these little things inside the

breast where the milk goes and the end

of the nipple comes through that little

tube when the baby sucks and we said

wonderful look at this pretty structure

we want to make this is structure and

ask the question how do the cells do

that so we took the red cells you see

the red cells are surrounded by blue

other cells that the squeeze them and

behind it is material that people

thought was mainly inert and it was just

having a structure to keep the shape and

so we first photographed it with the

electron microscope years and years ago

and you see the cell is actually quite

pretty it has a bottom it has a top it

is secreting gobs and gobs of milk

because he just came from an early

pregnant mouse you take these cells you

put them in a dish and within three days

is they look like that they completely

forget so you take them out you put them

in a dish they don’t make note they

completely forget for example here is a

lovely yellow droplet of milk on the

left there is nothing on the right look

at the nuclei the nuclei on the cell on

the left is in the animal the one on the

right is on a dish they are completely

different from each other so what does

this tell you this tells you that here

also context all the rights in different

contexts cells do different things but

harders contacts signal so Winston said

that for an idea that does not first

seem insane there is no hope so you can

imagine the amount of skepticism I

received couldn’t get money couldn’t do

a whole lot of other thing but I’m so

glad it all worked out so we made a

section of the mammary gland of the

mouse and all those lovely ass annoys

are there every one of those with the

red around them or an asst honest and we

said okay we are going to try and make

this and I said maybe that Redis stuff

around the asanas that people think

there is just a structural scaffold

maybe it has information maybe it tells

the cells what to do maybe it tells the

nucleus what to do so I said

extracellular matrix which is this stuff

called ECM signals and actually tells

the southward to do so we decided to

make things that would look like that we

found some gooey material that had the

right extracellular matrix in it we put

the cells in it and lo and behold in

about four days they got reorganized and

on the right is what we can make in

culture on the left is what’s inside the

animal we call it in vivo and the one in

culture was full of milk the lovely red

there is full of milk so we got milk for

the American audience all right

and here is this beautiful human cell

and you can imagine that here also the

context goes so what do we do now I made

a radical hypothesis I said if it’s true

that architecture is dominant

architecture restore to a cancer cell

should make the cancer cell think is

normal could this be done so we tried it

in order to do that however we needed to

have a method of distinguishing normal

from malignant and on the left is the

single normal cell human breast put in

three-dimensional gooey gel that has

extracellular matrix it makes all these

beautiful structure on the right you see

it looks very ugly the cells continue to

grow the normal ones stop and you see

here in higher magnification the normal

asanas and the ugly tumor so we said

what is on the surface of these oddly

tumors could we calmed them down they

were signaling like crazy and they have

pathways all messed up and make them to

the level of the normal well it was

wonderful boggles my mind this is what

we got we can revert the malignant

phenotype

and in order to show you that the

malignant phenotype I didn’t just choose

one here are little movies sort of fuzzy

but you see that on the left or the

malignant cells all of them are

malignant we add one single inhibitor at

the beginning and look what happens they

all look like that we inject them into

the mouse the ones on the right and none

of them would make tumors we inject the

other ones in the mouse hundred percent

tumors so the new way of thinking about

cancer is a hopeful way of thinking

about cancer we should be able to be

dealing with these things at this level

and these conclusions say that growth

and malignant behavior is regulated at

the level of tisch organization and that

the teacher organization is dependent on

the extracellular matrix and the micro

environment all right thus form and

function interact dynamically and

reciprocally and here is another

five-second of repose is why mantra form

and function and of course we now ask

where do we go now we like to take these

kind of thinking into the clinic but

before we do that I like you to think

that at any given time when you are

sitting there in your 70 trillion cells

the extracellular matrix signaling to

your nucleus the nucleus is signaling to

your extracellular matrix and that is

how your balance is kept and restored we

have made a lot of discoveries we have

shown that extracellular matrix talks to

chromatin we have shown that there are

little pieces of DNA on the specific

genes of the mammary gland that actually

respond to extracellular matrix it has

taken many years but it has been very

rewarding and before I get to their

necks aside I have to tell you that

there are so many additional discoveries

to be me

there is so much mystery we don’t know

and I always say to the student and

postdocs I lecture too don’t be arrogant

because arrogance kills curiosity

curiosity and passion you need to always

think what else is need to be discovered

and maybe my discovery needs to be added

to or maybe it needs to be changed so we

have now made an amazing discovery a

postdoc in the lab who is a physicist

asked me what did the cells do when you

put them in why did it what do they do

in the beginning when they they do i

said i don’t know we couldn’t look at

them we didn’t have high images in the

old days so she being an imager and

physicist did this incredible thing this

is a single human breath up in a tree

dimension look at it it’s constantly

doing this has a coherent movement you

put the cancer cells there and they do

go all over they do this they don’t do

this and when we revert the cancer cell

it again does this absolutely boggles my

mind so the cell acts like an embryo

what an exciting thing so I like to

finish with the poem but I used to love

English literature and I debated in

college which one should i do and

unfortunately or fortunately chemistry

one but here is a poem from yates i’ll

just read you the last two lines it’s

called among the schoolchildren or body

swayed to music or brightening glance

how do we tell the dancer from the dance

and here is Merce Cunningham I was

fortunate to dance with him when I was

younger and here he is a dancer and

while he’s dancing he’s both the dancer

and the dance the minute he stops we

have neither so is like form and

function now I like to show you a

current picture of my group I have been

fortunate to have had this magnificent

students and post doc who have taught me

so much and I have had many of these

scum angle they are the future and I try

to make them not be afraid of being the

cat and being told don’t think outside

the box and I’d like to leave you with

this thought on the left is water coming

through the shore taken from a NASA

satellite on the right there is a coral

now if you take the mammary gland and is

spread it and take the fat away on a

dish it looks like that do they look the

same do they have the same patterns why

is it that nature keeps doing that over

and over again and I’d like to submit to

you that we have sequence the human

genome we know everything about the

sequence of the gene the language of the

gene the alphabet of the gene but we

know nothing but nothing about the

language and alphabet of form so it’s a

wonderful new horizon it’s a wonderful

thing to discover for the young and the

passion as old and that’s me so go to it