Now, I don't usually like cartoons, I don't think many of them are funny, I find them weird. But I love this cartoon from the New Yorker.
Obično ne volim karikature, mislim da mnoge od njih nisu smešne, 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, 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 it's partly 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, or, for that matter, why you are who you are, didn't make sense.
Dakle, čovek govori mački, da se nisi usudila da razmišljaš van kutije. Bojim se da sam i ja nekad bila mačka. Uvek sam želela da budem van kutije. Delimično zbog toga što sam u ovu struku došla sa drugačijom pozadinom, kao hemičar i genetičar bakterija. Dakle, ono što su mi ljudi govorili o uzroku raka, poreklu raka ili uopšte, zašto ste takvi kakvi ste, nije imalo smisla.
So, let me quickly try and tell you why I thought 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 mom 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.
Dozvolite mi da pokušam brzo da vam kažem šta i kako sam o tome razmišljala. Međutim, da bih započela, moram vam dati veoma kratku lekciju iz razvojne biologije, uz izvinjenje onima koji znaju ponešto biologije. Kada su se vaši mama i tata sreli, stvara se oplođeno jaje, ta okrugla stvar sa tom malom tačkom. Ono raste i onda opet raste i onda postane ovaj zgodni čovek.
(Applause)
(Aplauz)
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 mammary cell. 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 with the same genetic material, make all those tissues? And so, the question I raised before becomes even more interesting if you thought about the enormity of this in every one of your bodies.
Ovaj čovek i sve ćelije u njegovom telu, imaju istu naslednu informaciju. Dakle, kako je njegov nos postao njegov nos, njegov lakat njegov lakat, i zašto se jednog jutra ne probudi sa nosem pretvorenim u stopalo? To je moguće. Za to nos ima naslednu informaciju. Svi se sećate, lučići, sve je nastalo iz jedne ćelije sisara. Pa, zašto se to ne dogodi? Pokušajte da pogodite koliko ćelija on ima u svom telu. Nešto između 10 i 70 biliona ćelija. Biliona! Kako su ove ćelije, sve sa istim naslednim materijalom, stvorile sva ta tkiva? Pitanje koje sam postavila ranije postaje još interesantnije, ako ste razmišljali o ogromnom broju ćelija u svakom od naših tela.
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 zeroes after zeroes after zeroes. Now, if .0001 of these cells got mutated, and .00001 got cancer, you will be a lump of cancer. You will have cancer all over you. And you're not. Why not?
Vladajuća teorija raka bi tvrdila da postoji jedan onkogen u jednoj ćeliji raka, koji će učiniti da postanete žrtva raka. Meni ovo nije imalo smisla. Da li uopšte znate kako bilion izgleda? Hajde da ga vidimo. Evo ga ovde, ove nule, posle nula, posle nula. Sada, ako jedna u deset hiljada od ovih ćelija mutira, a jedna u sto hiljada dobije rak, vi ćete biti grudva kancera. Imaćete kancer svuda po sebi. A vi to nemate. Zašto ne?
So, I decided over the years, because of a series of experiments that this is because of context and architecture.
Zaključila sam tokom godina, s obzirom na serije eksperimenata da je razlog za ovo kontekst i arhitektura.
And let me quickly tell you some crucial experiment that was able to actually show this. To begin with, I came to work with this virus that causes that ugly tumor in the chicken. Rous 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 the liquid after he passed the tumor through a filter, and he injected it to another chicken, and he got another tumor.
Dozvolite mi da vam brzo ispričam presudan ogled koji je uspeo ovo da dokaže. Da počnemo, počela sam da radim sa ovim virusom koji izaziva ovaj ružni tumor kod pilića. Ras ga je otkrio 1911. To je bio prvi otkriveni virus raka i kad ga nazovem ,,onkogen”, mislim na ,,gen raka”. On je napravio filtrat, uzeo je taj sadržaj odnosno tečnost, nakon što je tumor propustio kroz filter, ubrizgao ga je drugom piletu i dobio drugi tumor.
So, scientists were very excited, and they said, a single oncogene can do it. All you need is a single oncogene. So, they put the cells in cultures, chicken cells, dumped the virus on it, and it would pile up, and they would say, this is malignant and this is normal.
Naučnici su bili veoma uzbuđeni i rekli su, jedan onkogen to može da uradi. Sve što ti treba je jedan onkogen. Dakle, stavili su ćelije u kulture, pileće ćelije, istresli virus na njih, one bi se nagomilale, a oni su zaključili, ovo je maligno i ovo je normalno.
And again this didn't make sense to me. So for various reasons, we took this oncogene, attached it to a blue marker, and we injected it into the embryos. Now look at that. There is that beautiful 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 a mass of 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 microenvironment and the context which surrounds those cells actually are telling the cancer gene and the cancer cell what to do.
Ponovo ovo mi nije imalo smisla. Zbog toga smo iz različitih razloga, uzeli ovaj onkogen, vezali ga za plavi marker i ubrizgali ga u embrione. Sada pogledajte ovo. Tu je to divno pero u embrionu. Svaka od ovih plavih struktura je gen raka u ćeliji raka i one su deo pera. Kada smo izdvojili pero i stavili ga u posudu, dobili smo masu plavih ćelija. Tako, u piletu dobijete tumor, u embrionu ga ne dobijete, izdvojite ćelije, stavite ih u posudu i dobijete novi tumor. Šta ovo znači? To znači da mikrookolina i kontekst koji okružuje ove ćelije, u stvari govore genu raka i ćeliji raka šta da rade.
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 take just a bit of that mammary gland, which is called an "acinus," where 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.
Hajde da uzmemo normalan uzorak. Normalan uzorak, hajde da uzmemo ljudsku mlečnu žlezdu. Ja istražujem rak dojke. Ovde je krasna ljudska dojka. Mnogi od vas znaju kako ona izgleda, izuzev da unutar te dojke, postoje sve ove lepe, razvojne strukture koje podsećaju na drvo. Odlučili smo da ono što želimo da uradimo je da uzmemo samo delić te mlečne žlezde, koji se zove acinus, gde su sve ove male strukture unutar dojke gde prolazi mleko i kad beba sisa, izlazi kroz malu cev na vrhu bradavice.
And we said, wonderful! Look at this pretty structure. We want to make this a 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 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 this cell is actually quite pretty. It has a bottom, it has a top, it is secreting gobs and gobs of milk, because it just came from an early pregnant mouse.
Rekli smo, divno! Pogledajte ovu lepu strukturu. Želimo da stvorimo ovu strukturu i postavimo pitanje: ,,Kako te ćelije to rade?” Uzeli smo crvene ćelije -- vidite crvene ćelije okružene plavima, drugim ćelijama koje ih pritiskaju, a iza toga je materijal za koji su ljudi mislili da je uglavnom neaktivan i da ima strukturu samo da bi se održavao oblik, prvo smo ga fotografisali elektronskim mikroskopom pre mnogo godina i vidite da je ova ćelija u stvari prilično lepa. Ima dno, ima vrh i izlučuje velike količine mleka, jer su poreklom od miša u ranoj trudnoći.
You take these cells, you put them in a dish, and within three days, they look like that. They completely forget. So you take them out, you put them in a dish, they don't make milk. 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 in the cell on the left is in the animal, the one on the right is in a dish. They are completely different from each other.
Uzmete ove ćelije, stavite ih u posudu i nakon tri dana, one izgledaju ovako. One potpuno zaborave. Dakle, izvadite ih, stavite ih u posudu i one ne proizvode mleko. Potpuno zaborave. Na primer, ovde je lepa žuta kap mleka sa leve strane, nema ništa sa desne strane. Pogledajte jedra. Jedra ćelija sa leve strane su u životinji, ona sa desne su u posudi. Potpuno su različita.
So, what does this tell you? This tells you that here also, context overrides. In different contexts, cells do different things. But how does context signal? So, Einstein 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 things, but I'm so glad it all worked out.
Šta vam to govori? Ovo vam govori da i u ovom slučaju, kontekst nadvladava. U različitim kontekstima, ćelije rade različite stvari. Ali kako kontekst daje signale? Ajnštajn je rekao: ,,Za ideju koja u početku ne izgleda ludo, nema nade.” Možete zamisliti koliko sam sumnjičavosti doživela -- nisam mogla da dobijem novac, nisam mogla da uradim mnoge druge stvari. Ali mi je tako drago da se sve razrešilo.
So, we made a section of the mammary gland of the mouse, and all those lovely acini are there, every one of those with the red around them are an acinus, and we said okay, we are going to try and make this, and I said, maybe that red stuff around the acinus that people think there's 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 cells what to do.
Napravili smo presek mlečne žlezde miša, svi ti divni acinusi su tu, svaki ovaj sa crvenim u okolini je acinus, rekli smo dobro, pokušaćemo da ga napravimo i ja sam pomislila, možda taj crveni materijal oko acinusa koji ljudi smatraju samo strukturnim skeletom, možda on ima informaciju, možda on govori ćeliji šta da radi, možda on govori jedru šta da radi. Rekla sam, vanćelijski matriks, što je ova stvar, skraćeno ECM, koja signalizira i u stvari govori ćeliji šta da radi.
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, context goes.
Odlučili smo da napravimo nešto što bi tako izgledalo. Našli smo neki gnjecav materijal koji je imao u sebi odgovarajući vanćelijski matriks, stavili smo ćelije u njega, gledaj i vidi za otprilike četiri dana, one su se preuredile i desno je ono što možemo dobiti u kulturi. Levo vidite šta je u životinji, zovemo ga in vivo, one u kulturi su bile pune mleka, lepe crvene su pune mleka. Tako smo dobili mleko, za američku publiku. U redu. Ovde je divna ljudska ćelija, možete da zamislite, da je i ovde kontekst bitan.
So, what do we do now? I made a radical hypothesis. I said, if it's true that architecture is dominant, architecture restored to a cancer cell should make the cancer cell think it's 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 structures. 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 acinus and the ugly tumor.
Pa, šta sad da radimo? Napravila sam radikalnu hipotezu. Rekla sam, ako je tačno da je arhitektura dominantna, onda bi obnovljena arhitektura trebalo da utiče na ćeliju raka, da ćelija raka misli da je normalna. Da li bi se ovo moglo učiniti? Pokušali smo. Međutim, da bi ovo učinili, trebao nam je metod razlikovanja normalnog od malignog, levo je pojedinačna normalna ćelija ljudske dojke, stavljena u trodimenzionalni gnjecavi gel koji ima vanćelijski matriks, ćelija pravi sve te divne strukture. Sa desne strane, vidite da izgleda veoma ružno, ćelije nastavljaju da rastu, dok normalne prestaju. Ovde pod većim uvećanjem vidite normalan acinus i ružni tumor.
So we said, what is on the surface of these ugly tumors? Could we calm 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.
Pitali smo, šta je na površini ovih ružnih tumora? Možemo li da ih smirimo -- šalju signale kao poludele i imaju potpuno zamršene puteve -- i vratimo ih na nivo normalnih ćelija? Pa, to je bilo divno. Čudnovato. Ovo smo dobili. Možemo da preokrenemo maligni fenotip.
(Applause)
(Aplauz)
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 are the malignant cells, all of them are malignant, we add one single inhibitor in 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, 100 percent tumors.
Da bih vam pokazala taj maligni fenotip nisam izabrala samo jedan, ovde su kratki filmovi, pomalo zamućeni, ali levo možete videti maligne ćelije, sve su one maligne, dodali smo jedan inhibitor na početku i pogledajte šta se događa, sve one izgledaju tako. Ubrizgali smo ih u miša, one sa desne strane i nijedna nije htela da napravili tumore. Ubrizgali smo one druge u miša, sto posto tumori.
So, it's a new way of thinking about cancer, it's 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 tissue organization and that the tissue organization is dependent on the extracellular matrix and the microenvironment. All right, thus form and function interact dynamically and reciprocally. And here is another five seconds of repose, is my mantra. Form and function.
To je novi način razmišljanja o kanceru, to je način razmišljanja o kanceru koji daje nadu. Trebalo bi da možemo da rešavamo ove probleme na sadašnjem nivou i ovi zaključci govore da su rast i maligno ponašanje regulisani na nivou organizacije tkiva, da je ova organizacija tkiva zavisna od vanćelijskog matriksa i mikrookoline. Prema tome, forma i funkcija deluju dinamično i uzajamno, Ovde je dodatnih pet sekundi pauze, moja mantra. Forma i funkcija.
And of course, we now ask, where do we go now? We'd like to take this kind of thinking into the clinic. But before we do that, I'd like you to think that at any given time when you're sitting there, in your 70 trillion cells, the extracellular matrix signaling to your nucleus, the nucleus is signaling to your extracellular matrix and this is how your balance is kept and restored.
Svakako, pitamo se, u kom pravcu sada da idemo? Želeli bismo da prenesemo ovaj način razmišljanja u praksu. Ali pre nego što to uradimo, volela bih da razmislite da u svakom trenutku dok ovde sedite, u vaših 70 biliona ćelija, vanćelijski matriks signalizira vašem jedru, jedro signalizira vašem vanćelijskom matriksu i to je način kako se vaša ravnoteža uspostavlja i održava.
We have made a lot of discoveries, we have shown that extracellular matrix talks to chromatin. We have shown that there's 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.
Napravili smo mnoga otkrića, pokazali smo da vanćelijski matriks razgovara sa hromatinom. Pokazali smo da postoje mali delovi DNK, specifični geni mlečne žlezde, koji u stvari reaguju na vanćelijski matriks. Bilo je potrebno mogo godina, ali je bilo veoma korisno.
And before I get to the next slide, I have to tell you that there are so many additional discoveries to be made. There is so much mystery we don't know. And I always say to the students and post-docs I lecture to, don't be arrogant, because arrogance kills curiosity. Curiosity and passion. You need to always think, what else needs to be discovered? And maybe my discovery needs to be added to or maybe it needs to be changed.
Pre nego što pređem na sledeći slajd, moram da vam kažem da postoji još mnogo dodatnih otkrića. Postoji toliko tajanstvenog što ne znamo. Uvek kažem studentima i postdiplomcima kojima predajem, ne budite uobraženi, jer uobraženost ubija znatiželju. Znatiželja i žar. Uvek treba da mislite, šta još treba da se otkrije? Možda mom otkriću treba nešto dodati ili ga treba menjati.
So, we have now made an amazing discovery, a post-doc in the lab who is a physicist asked me, what do the cells do when you put them in? What do they do in the beginning when 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 a physicist, did this incredible thing. This is a single human breast cell in three dimensions. 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.
Upravo smo napravili neverovatno oktriće, doktorantkinja u laboratoriji, koja je fizičar, me je pitala šta ove ćelije rade kad ih stavite u posudu? Šta rade na početku aktivnosti? Rekla sam da ne znam, nismo mogli da ih gledamo. Nismo imali slike visoke rezolucije u starim danima. Tako je ona, s obzirom da je mikroskopista i fizičar, uradila nešto neverovatno. Ovo je pojedinačna ćelija ljudske dojke u tri dimenzije. Pogledajte je. Ona konstantno radi ovo. Ima skladan pokret. Ako tu stavite ćelije raka, one se kreću svuda, one rade ovo. One ne rade ovo. A kada preokrenemo ćeliju raka, ona opet radi ovo. Apsolutno me začuđuje. Dakle, ćelije se ponašaju kao embrion. Kako uzbudljivo.
So I'd like to finish with a poem. Well I used to love English literature, and I debated in college, which one should I do? And unfortunately or fortunately, chemistry won. But here is a poem from Yeats. I'll just read you the last two lines. It's called "Among the School Children." "O body swayed to music / O brightening glance / How [can we know] 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 is dancing, he is both the dancer and the dance. The minute he stops, we have neither. So it's like form and function.
Volela bih da završim sa stihovima. Volela sam englesku književnost, i razmišljala sam na koledžu šta bi trebalo da radim? Na sreću ili na nesreću, pobedila je hemija. Ovde je Jejtsova pesma. Pročitaću vam samo poslednja dva stiha. Zove se “Među školarcima”. O telo što uz muziku se njiše Vedrog oka bles Kako od plesača razlučiti ples. (preveo Igor Popov) O telo što uz muziku se njiše Vedrog oka bles Kako od plesača razlučiti ples. (preveo Igor Popov) Ovo je Mers Kaninghem. Imala sam sreću da plešem sa njim kad sam bila mlađa, ovde je plesač, dok pleše, on je istovremeno plesač i ples. Onog trenutka kad prestane, nemamo ni jedno. To je kao forma I funkcija.
Now, I'd like to show you a current picture of my group. I have been fortunate to have had these magnificant students and post-docs who have taught me so much, and I have had many of these groups come and go. 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.
Sada, želela bih da vam pokažem sadašnju fotografiju moje grupe. Imala sam sreću da imam ove sjajne studente i postdiplomce koji su me toliko naučili, imala sam mnogo ovakvih grupa koje su došle i prošle. Oni su budućnost i trudim se da ih naučim da se ne uplaše da budu mačka i kad im se kaže da ne misle van uobičajenog.
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 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?
Volela bih da vas ostavim sa ovim razmišljanjem. Sa leve strane je voda koja dolazi na obalu, slikano iz NASA satelita. Desno je koral. Sada ako uzmete mlečnu žlezdu i napravite preparat, oduzimajući masno tkivo, u posudi ona izgleda ovako. Da li izgledaju isto? Da li imaju iste obrasce? Zašto priroda uvek iznova radi ovo?
And I'd like to submit to you that we have sequenced 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 passionate old, and that's me.
Htela bih da vam predočim da smo odredili ljudski genom, znamo sve o redosledu gena, jeziku gena, abecedi gena. Ali ne znamo ništa, baš ništa, o jeziku i abecedi forme. To je divni novi horizont, to je divna nova stvar da je otkriju mladi i pasionirani stariji, kao ja.
So go to it!
Pa idite ka tome!
(Applause)
(Aplauz)