Mina Bissell: Experiments that point to a new understanding of cancer

Translator: Morton Bast Reviewer: Thu-Huong Ha

Prevodilac: Tatjana Jevdjic Lektor: Stevan S.

Now, I don't usually like cartoons,

Obično ne volim karikature,

I don't think many of them are funny,

mislim da mnoge od njih nisu smešne,

I find them weird. But I love this cartoon from the New Yorker.

nalazim da su čudne. Ali, volim ovu karikaturu iz New Yorker-a.

(Text: Never, ever think outside the box.) (Laughter)

(Tekst: Nikad, nikad ne razmišljaj izvan kutije) (Smeh)

So, the guy is telling the cat,

Dakle, čovek govori mački,

don't you dare think outside the box.

da se nisi usudila da razmišljaš van kutije.

Well, I'm afraid I used to be the cat.

Bojim se da sam i ja nekad bila mačka.

I always wanted to be outside the box.

Uvek sam želela da budem van kutije.

And it's partly because I came to this field

Delimično zbog toga što sam u ovu struku došla

from a different background, chemist and a bacterial geneticist.

sa drugačijom pozadinom, kao hemičar i genetičar bakterija.

So, what people were saying to me

Dakle, ono što su mi ljudi govorili

about the cause of cancer, sources of cancer,

o uzroku raka, poreklu raka

or, for that matter, why you are who you are,

ili uopšte, zašto ste takvi kakvi ste,

didn't make sense.

nije imalo smisla.

So, let me quickly try and tell you why I thought that

Dozvolite mi da pokušam brzo da vam kažem

and how I went about it.

šta i kako sam o tome razmišljala.

So, to begin with, however,

Međutim, da bih započela,

I have to give you a very, very quick lesson

moram vam dati veoma kratku lekciju

in developmental biology,

iz razvojne biologije,

with apologies to those of you who know some biology.

uz izvinjenje onima koji znaju ponešto biologije.

So, when your mom and dad met,

Kada su se vaši mama i tata sreli,

there is a fertilized egg,

stvara se oplođeno jaje,

that round thing with that little blip.

ta okrugla stvar sa tom malom tačkom.

It grows and then it grows,

Ono raste i onda opet raste

and then it makes this handsome man.

i onda postane ovaj zgodni čovek.

(Applause)

(Aplauz)

So, this guy, with all the cells in his body,

Ovaj čovek i sve ćelije u njegovom telu,

all have the same genetic information.

imaju istu naslednu informaciju.

So how did his nose become his nose, his elbow his elbow,

Dakle, kako je njegov nos postao njegov nos, njegov lakat njegov lakat,

and why doesn't he get up one morning

i zašto se jednog jutra ne probudi

and have his nose turn into his foot?

sa nosem pretvorenim u stopalo?

It could. It has the genetic information.

To je moguće. Za to nos ima naslednu informaciju.

You all remember, dolly,

Svi se sećate, lučići,

it came from a single mammary cell.

sve je nastalo iz jedne ćelije sisara.

So, why doesn't it do it?

Pa, zašto se to ne dogodi?

So, have a guess of how many cells he has in his body.

Pokušajte da pogodite koliko ćelija on ima u svom telu.

Somewhere between 10 trillion to 70 trillion cells in his body.

Nešto između 10 i 70 biliona ćelija.

Trillion!

Biliona!

Now, how did these cells, all with the same genetic material,

Kako su ove ćelije, sve sa istim naslednim materijalom,

make all those tissues?

stvorile sva ta tkiva?

And so, the question I raised before

Pitanje koje sam postavila ranije

becomes even more interesting if you thought about

postaje još interesantnije, ako ste razmišljali o

the enormity of this in every one of your bodies.

ogromnom broju ćelija u svakom od naših tela.

Now, the dominant cancer theory would say

Vladajuća teorija raka bi tvrdila

that there is a single oncogene

da postoji jedan onkogen

in a single cancer cell, and it would make you

u jednoj ćeliji raka, koji će učiniti da postanete

a cancer victim.

žrtva raka.

Well, this did not make sense to me.

Meni ovo nije imalo smisla.

Do you even know how a trillion looks?

Da li uopšte znate kako bilion izgleda?

Now, let's look at it.

Hajde da ga vidimo.

There it comes, these zeroes after zeroes after zeroes.

Evo ga ovde, ove nule, posle nula, posle nula.

Now, if .0001 of these cells got mutated,

Sada, ako jedna u deset hiljada od ovih ćelija mutira,

and .00001 got cancer, you will be a lump of cancer.

a jedna u sto hiljada dobije rak, vi ćete biti grudva kancera.

You will have cancer all over you. And you're not.

Imaćete kancer svuda po sebi. A vi to nemate.

Why not?

Zašto ne?

So, I decided over the years,

Zaključila sam tokom godina,

because of a series of experiments

s obzirom na serije eksperimenata

that this is because of context and architecture.

da je razlog za ovo kontekst i arhitektura.

And let me quickly tell you

Dozvolite mi da vam brzo ispričam

some crucial experiment that was able to actually show this.

presudan ogled koji je uspeo ovo da dokaže.

To begin with, I came to work with this virus

Da počnemo, počela sam da radim sa ovim virusom

that causes that ugly tumor in the chicken.

koji izaziva ovaj ružni tumor kod pilića.

Rous discovered this in 1911.

Ras ga je otkrio 1911.

It was the first cancer virus discovered,

To je bio prvi otkriveni virus raka

and when I call it "oncogene," meaning "cancer gene."

i kad ga nazovem ,,onkogen”, mislim na ,,gen raka”.

So, he made a filtrate, he took this filter

On je napravio filtrat, uzeo je taj sadržaj

which was the liquid after he passed the tumor through a filter,

odnosno tečnost, nakon što je tumor propustio kroz filter,

and he injected it to another chicken, and he got another tumor.

ubrizgao ga je drugom piletu i dobio drugi tumor.

So, scientists were very excited,

Naučnici su bili veoma uzbuđeni

and they said, a single oncogene can do it.

i rekli su, jedan onkogen to može da uradi.

All you need is a single oncogene.

Sve što ti treba je jedan onkogen.

So, they put the cells in cultures, chicken cells,

Dakle, stavili su ćelije u kulture, pileće ćelije,

dumped the virus on it,

istresli virus na njih,

and it would pile up,

one bi se nagomilale,

and they would say, this is malignant and this is normal.

a oni su zaključili, ovo je maligno i ovo je normalno.

And again this didn't make sense to me.

Ponovo ovo mi nije imalo smisla.

So for various reasons, we took this oncogene,

Zbog toga smo iz različitih razloga, uzeli ovaj onkogen,

attached it to a blue marker,

vezali ga za plavi marker

and we injected it into the embryos.

i ubrizgali ga u embrione.

Now look at that. There is that beautiful feather in the embryo.

Sada pogledajte ovo. Tu je to divno pero u embrionu.

Every one of those blue cells are a cancer gene

Svaka od ovih plavih struktura je gen raka

inside a cancer cell, and they're part of the feather.

u ćeliji raka i one su deo pera.

So, when we dissociated the feather and put it in a dish,

Kada smo izdvojili pero i stavili ga u posudu,

we got a mass of blue cells.

dobili smo masu plavih ćelija.

So, in the chicken you get a tumor,

Tako, u piletu dobijete tumor,

in the embryo you don't,

u embrionu ga ne dobijete,

you dissociate, you put it in a dish, you get another tumor.

izdvojite ćelije, stavite ih u posudu i dobijete novi tumor.

What does that mean?

Šta ovo znači?

That means that microenvironment

To znači da mikrookolina

and the context which surrounds those cells

i kontekst koji okružuje ove ćelije,

actually are telling the cancer gene and the cancer cell what to do.

u stvari govore genu raka i ćeliji raka šta da rade.

Now, let's take a normal example.

Hajde da uzmemo normalan uzorak.

The normal example, let's take the human mammary gland.

Normalan uzorak, hajde da uzmemo ljudsku mlečnu žlezdu.

I work on breast cancer.

Ja istražujem rak dojke.

So, here is a lovely human breast.

Ovde je krasna ljudska dojka.

And many of you know how it looks,

Mnogi od vas znaju kako ona izgleda,

except that inside that breast, there are all these

izuzev da unutar te dojke, postoje sve ove

pretty, developing, tree-like structures.

lepe, razvojne strukture koje podsećaju na drvo.

So, we decided that what we like to do

Odlučili smo da ono što želimo da uradimo

is take just a bit of that mammary gland,

je da uzmemo samo delić te mlečne žlezde,

which is called an "acinus,"

koji se zove acinus,

where there are all these little things inside the breast

gde su sve ove male strukture unutar dojke

where the milk goes, and the end of the nipple

gde prolazi mleko i kad beba sisa, izlazi

comes through that little tube when the baby sucks.

kroz malu cev na vrhu bradavice.

And we said, wonderful! Look at this pretty structure.

Rekli smo, divno! Pogledajte ovu lepu strukturu.

We want to make this a structure, and ask the question,

Želimo da stvorimo ovu strukturu i postavimo pitanje:

how do the cells do that?

,,Kako te ćelije to rade?”

So, we took the red cells --

Uzeli smo crvene ćelije --

you see the red cells are surrounded by blue,

vidite crvene ćelije okružene plavima,

other cells that squeeze them, and behind it

drugim ćelijama koje ih pritiskaju, a iza toga je

is material that people thought was mainly inert,

materijal za koji su ljudi mislili da je uglavnom neaktivan

and it was just having a structure to keep the shape,

i da ima strukturu samo da bi se održavao oblik,

and so we first photographed it

prvo smo ga fotografisali

with the electron microscope years and years ago,

elektronskim mikroskopom pre mnogo godina

and you see this cell is actually quite pretty.

i vidite da je ova ćelija u stvari prilično lepa.

It has a bottom, it has a top,

Ima dno, ima vrh

it is secreting gobs and gobs of milk,

i izlučuje velike količine mleka,

because it just came from an early pregnant mouse.

jer su poreklom od miša u ranoj trudnoći.

You take these cells, you put them in a dish,

Uzmete ove ćelije, stavite ih u posudu

and within three days, they look like that.

i nakon tri dana, one izgledaju ovako.

They completely forget.

One potpuno zaborave.

So you take them out, you put them in a dish,

Dakle, izvadite ih, stavite ih u posudu

they don't make milk. They completely forget.

i one ne proizvode mleko. Potpuno zaborave.

For example, here is a lovely yellow droplet of milk

Na primer, ovde je lepa žuta kap mleka

on the left, there is nothing on the right.

sa leve strane, nema ništa sa desne strane.

Look at the nuclei. The nuclei in the cell on the left

Pogledajte jedra. Jedra ćelija sa leve strane

is in the animal, the one on the right is in a dish.

su u životinji, ona sa desne su u posudi.

They are completely different from each other.

Potpuno su različita.

So, what does this tell you?

Šta vam to govori?

This tells you that here also, context overrides.

Ovo vam govori da i u ovom slučaju, kontekst nadvladava.

In different contexts, cells do different things.

U različitim kontekstima, ćelije rade različite stvari.

But how does context signal?

Ali kako kontekst daje signale?

So, Einstein said that

Ajnštajn je rekao:

"For an idea that does not first seem insane, there is no hope."

,,Za ideju koja u početku ne izgleda ludo, nema nade.”

So, you can imagine the amount of skepticism

Možete zamisliti koliko sam sumnjičavosti

I received -- couldn't get money,

doživela -- nisam mogla da dobijem novac,

couldn't do a whole lot of other things,

nisam mogla da uradim mnoge druge stvari.

but I'm so glad it all worked out.

Ali mi je tako drago da se sve razrešilo.

So, we made a section of the mammary gland of the mouse,

Napravili smo presek mlečne žlezde miša,

and all those lovely acini are there,

svi ti divni acinusi su tu,

every one of those with the red around them are an acinus,

svaki ovaj sa crvenim u okolini je acinus,

and we said okay, we are going to try and make this,

rekli smo dobro, pokušaćemo da ga napravimo

and I said, maybe that red stuff

i ja sam pomislila, možda taj crveni materijal

around the acinus that people think there's just a structural scaffold,

oko acinusa koji ljudi smatraju samo strukturnim skeletom,

maybe it has information,

možda on ima informaciju,

maybe it tells the cells what to do, maybe it tells the nucleus what to do.

možda on govori ćeliji šta da radi, možda on govori jedru šta da radi.

So I said, extracellular matrix, which is this stuff

Rekla sam, vanćelijski matriks, što je ova stvar,

called ECM, signals and actually tells the cells what to do.

skraćeno ECM, koja signalizira i u stvari govori ćeliji šta da radi.

So, we decided to make things that would look like that.

Odlučili smo da napravimo nešto što bi tako izgledalo.

We found some gooey material

Našli smo neki gnjecav materijal

that had the right extracellular matrix in it,

koji je imao u sebi odgovarajući vanćelijski matriks,

we put the cells in it, and lo and behold,

stavili smo ćelije u njega, gledaj i vidi

in about four days, they got reorganized

za otprilike četiri dana, one su se preuredile

and on the right, is what we can make in culture.

i desno je ono što možemo dobiti u kulturi.

On the left is what's inside the animal, we call it in vivo,

Levo vidite šta je u životinji, zovemo ga in vivo,

and the one in culture was full of milk,

one u kulturi su bile pune mleka,

the lovely red there is full of milk.

lepe crvene su pune mleka.

So, we Got Milk, for the American audience.

Tako smo dobili mleko, za američku publiku.

All right. And here is this beautiful human cell,

U redu. Ovde je divna ljudska ćelija,

and you can imagine that here also, context goes.

možete da zamislite, da je i ovde kontekst bitan.

So, what do we do now?

Pa, šta sad da radimo?

I made a radical hypothesis.

Napravila sam radikalnu hipotezu.

I said, if it's true that architecture is dominant,

Rekla sam, ako je tačno da je arhitektura dominantna,

architecture restored to a cancer cell

onda bi obnovljena arhitektura trebalo da utiče

should make the cancer cell think it's normal.

na ćeliju raka, da ćelija raka misli da je normalna.

Could this be done?

Da li bi se ovo moglo učiniti?

So, we tried it.

Pokušali smo.

In order to do that, however,

Međutim, da bi ovo učinili,

we needed to have a method of distinguishing normal from malignant,

trebao nam je metod razlikovanja normalnog od malignog,

and on the left is the single normal cell,

levo je pojedinačna normalna ćelija

human breast, put in three-dimensional gooey gel

ljudske dojke, stavljena u trodimenzionalni gnjecavi gel

that has extracellular matrix, it makes all these beautiful structures.

koji ima vanćelijski matriks, ćelija pravi sve te divne strukture.

On the right, you see it looks very ugly,

Sa desne strane, vidite da izgleda veoma ružno,

the cells continue to grow,

ćelije nastavljaju da rastu,

the normal ones stop.

dok normalne prestaju.

And you see here in higher magnification

Ovde pod većim uvećanjem vidite

the normal acinus and the ugly tumor.

normalan acinus i ružni tumor.

So we said, what is on the surface of these ugly tumors?

Pitali smo, šta je na površini ovih ružnih tumora?

Could we calm them down --

Možemo li da ih smirimo --

they were signaling like crazy and they have pathways all messed up --

šalju signale kao poludele i imaju potpuno zamršene puteve --

and make them to the level of the normal?

i vratimo ih na nivo normalnih ćelija?

Well, it was wonderful. Boggles my mind.

Pa, to je bilo divno. Čudnovato.

This is what we got.

Ovo smo dobili.

We can revert the malignant phenotype.

Možemo da preokrenemo maligni fenotip.

(Applause)

(Aplauz)

And in order to show you that the malignant phenotype

Da bih vam pokazala taj maligni fenotip

I didn't just choose one,

nisam izabrala samo jedan,

here are little movies, sort of fuzzy,

ovde su kratki filmovi, pomalo zamućeni,

but you see that on the left are the malignant cells,

ali levo možete videti maligne ćelije,

all of them are malignant,

sve su one maligne,

we add one single inhibitor in the beginning,

dodali smo jedan inhibitor na početku

and look what happens, they all look like that.

i pogledajte šta se događa, sve one izgledaju tako.

We inject them into the mouse, the ones on the right,

Ubrizgali smo ih u miša, one sa desne strane

and none of them would make tumors.

i nijedna nije htela da napravili tumore.

We inject the other ones in the mouse, 100 percent tumors.

Ubrizgali smo one druge u miša, sto posto tumori.

So, it's a new way of thinking about cancer,

To je novi način razmišljanja o kanceru,

it's a hopeful way of thinking about cancer.

to je način razmišljanja o kanceru koji daje nadu.

We should be able to be dealing with these things at this level,

Trebalo bi da možemo da rešavamo ove probleme na sadašnjem nivou

and these conclusions say that growth and malignant behavior

i ovi zaključci govore da su rast i maligno ponašanje

is regulated at the level of tissue organization

regulisani na nivou organizacije tkiva,

and that the tissue organization is dependent

da je ova organizacija tkiva zavisna

on the extracellular matrix and the microenvironment.

od vanćelijskog matriksa i mikrookoline.

All right, thus form and function interact dynamically and reciprocally.

Prema tome, forma i funkcija deluju dinamično i uzajamno,

And here is another five seconds of repose,

Ovde je dodatnih pet sekundi pauze,

is my mantra. Form and function.

moja mantra. Forma i funkcija.

And of course, we now ask, where do we go now?

Svakako, pitamo se, u kom pravcu sada da idemo?

We'd like to take this kind of thinking into the clinic.

Želeli bismo da prenesemo ovaj način razmišljanja u praksu.

But before we do that, I'd like you to think

Ali pre nego što to uradimo, volela bih da razmislite

that at any given time when you're sitting there,

da u svakom trenutku dok ovde sedite,

in your 70 trillion cells,

u vaših 70 biliona ćelija,

the extracellular matrix signaling to your nucleus,

vanćelijski matriks signalizira vašem jedru,

the nucleus is signaling to your extracellular matrix

jedro signalizira vašem vanćelijskom matriksu

and this is how your balance is kept and restored.

i to je način kako se vaša ravnoteža uspostavlja i održava.

We have made a lot of discoveries,

Napravili smo mnoga otkrića,

we have shown that extracellular matrix talks to chromatin.

pokazali smo da vanćelijski matriks razgovara sa hromatinom.

We have shown that there's little pieces of DNA

Pokazali smo da postoje mali delovi DNK,

on the specific genes of the mammary gland

specifični geni mlečne žlezde,

that actually respond to extracellular matrix.

koji u stvari reaguju na vanćelijski matriks.

It has taken many years, but it has been very rewarding.

Bilo je potrebno mogo godina, ali je bilo veoma korisno.

And before I get to the next slide, I have to tell you

Pre nego što pređem na sledeći slajd, moram da vam kažem

that there are so many additional discoveries to be made.

da postoji još mnogo dodatnih otkrića.

There is so much mystery we don't know.

Postoji toliko tajanstvenog što ne znamo.

And I always say to the students and post-docs I lecture to,

Uvek kažem studentima i postdiplomcima kojima predajem,

don't be arrogant, because arrogance kills curiosity.

ne budite uobraženi, jer uobraženost ubija znatiželju.

Curiosity and passion.

Znatiželja i žar.

You need to always think, what else needs to be discovered?

Uvek treba da mislite, šta još treba da se otkrije?

And maybe my discovery needs to be added to

Možda mom otkriću treba nešto dodati

or maybe it needs to be changed.

ili ga treba menjati.

So, we have now made an amazing discovery,

Upravo smo napravili neverovatno oktriće,

a post-doc in the lab who is a physicist asked me,

doktorantkinja u laboratoriji, koja je fizičar, me je pitala

what do the cells do when you put them in?

šta ove ćelije rade kad ih stavite u posudu?

What do they do in the beginning when they do?

Šta rade na početku aktivnosti?

I said, I don't know, we couldn't look at them.

Rekla sam da ne znam, nismo mogli da ih gledamo.

We didn't have high images in the old days.

Nismo imali slike visoke rezolucije u starim danima.

So she, being an imager and a physicist,

Tako je ona, s obzirom da je mikroskopista i fizičar,

did this incredible thing.

uradila nešto neverovatno.

This is a single human breast cell in three dimensions.

Ovo je pojedinačna ćelija ljudske dojke u tri dimenzije.

Look at it. It's constantly doing this.

Pogledajte je. Ona konstantno radi ovo.

Has a coherent movement.

Ima skladan pokret.

You put the cancer cells there, and they do go all over,

Ako tu stavite ćelije raka, one se kreću svuda,

they do this. They don't do this.

one rade ovo. One ne rade ovo.

And when we revert the cancer cell, it again does this.

A kada preokrenemo ćeliju raka, ona opet radi ovo.

Absolutely boggles my mind.

Apsolutno me začuđuje.

So the cell acts like an embryo. What an exciting thing.

Dakle, ćelije se ponašaju kao embrion. Kako uzbudljivo.

So I'd like to finish with a poem.

Volela bih da završim sa stihovima.

Well I used to love English literature,

Volela sam englesku književnost,

and I debated in college, which one should I do?

i razmišljala sam na koledžu šta bi trebalo da radim?

And unfortunately or fortunately, chemistry won.

Na sreću ili na nesreću, pobedila je hemija.

But here is a poem from Yeats. I'll just read you the last two lines.

Ovde je Jejtsova pesma. Pročitaću vam samo poslednja dva stiha.

It's called "Among the School Children."

Zove se “Među školarcima”.

"O body swayed to music / O brightening glance /

O telo što uz muziku se njiše Vedrog oka bles Kako od plesača razlučiti ples. (preveo Igor Popov)

How [can we know] the dancer from the dance?"

O telo što uz muziku se njiše Vedrog oka bles Kako od plesača razlučiti ples. (preveo Igor Popov)

And here is Merce Cunningham,

Ovo je Mers Kaninghem.

I was fortunate to dance with him when I was younger,

Imala sam sreću da plešem sa njim kad sam bila mlađa,

and here he is a dancer,

ovde je plesač,

and while he is dancing, he is both the dancer and the dance.

dok pleše, on je istovremeno plesač i ples.

The minute he stops, we have neither.

Onog trenutka kad prestane, nemamo ni jedno.

So it's like form and function.

To je kao forma I funkcija.

Now, I'd like to show you a current picture of my group.

Sada, želela bih da vam pokažem sadašnju fotografiju moje grupe.

I have been fortunate to have had these magnificant

Imala sam sreću da imam ove sjajne

students and post-docs who have taught me so much,

studente i postdiplomce koji su me toliko naučili,

and I have had many of these groups come and go.

imala sam mnogo ovakvih grupa koje su došle i prošle.

They are the future and I try to make them not be afraid

Oni su budućnost i trudim se da ih naučim da se ne uplaše

of being the cat and being told,

da budu mačka i kad im se kaže

don't think outside the box.

da ne misle van uobičajenog.

And I'd like to leave you with this thought.

Volela bih da vas ostavim sa ovim razmišljanjem.

On the left is water coming through the shore,

Sa leve strane je voda koja dolazi na obalu,

taken from a NASA satellite.

slikano iz NASA satelita.

On the right, there is a coral.

Desno je koral.

Now if you take the mammary gland and spread it

Sada ako uzmete mlečnu žlezdu i napravite preparat,

and take the fat away, on a dish it looks like that.

oduzimajući masno tkivo, u posudi ona izgleda ovako.

Do they look the same? Do they have the same patterns?

Da li izgledaju isto? Da li imaju iste obrasce?

Why is it that nature keeps doing that over and over again?

Zašto priroda uvek iznova radi ovo?

And I'd like to submit to you

Htela bih da vam predočim

that we have sequenced the human genome,

da smo odredili ljudski genom,

we know everything about the sequence of the gene,

znamo sve o redosledu gena,

the language of the gene, the alphabet of the gene,

jeziku gena, abecedi gena.

But we know nothing, but nothing,

Ali ne znamo ništa, baš ništa,

about the language and alphabet of form.

o jeziku i abecedi forme.

So, it's a wonderful new horizon,

To je divni novi horizont,

it's a wonderful thing to discover for the young

to je divna nova stvar da je otkriju mladi

and the passionate old, and that's me.

i pasionirani stariji, kao ja.

So go to it!

Pa idite ka tome!

(Applause)

(Aplauz)