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Now, I don't usually like cartoons,

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I don't think many of them are funny,

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

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

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So, the guy is telling the cat,

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don't you dare think outside the box.

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

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I always wanted to be outside the box.

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And it's partly because I came to this field

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from a different background, chemist and a bacterial geneticist.

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So, what people were saying to me

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about the cause of cancer, sources of cancer,

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

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didn't make sense.

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

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and how I went about it.

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So, to begin with, however,

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I have to give you a very, very quick lesson

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in developmental biology,

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with apologies to those of you who know some biology.

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So, when your mom and dad met,

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there is a fertilized egg,

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that round thing with that little blip.

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It grows and then it grows,

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and then it makes this handsome man.

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(Applause)

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

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all have the same genetic information.

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

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and why doesn't he get up one morning

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and have his nose turn into his foot?

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It could. It has the genetic information.

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You all remember, dolly,

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it came from a single mammary cell.

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So, why doesn't it do it?

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

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

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Trillion!

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

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make all those tissues?

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And so, the question I raised before

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becomes even more interesting if you thought about

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the enormity of this in every one of your bodies.

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Now, the dominant cancer theory would say

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that there is a single oncogene

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in a single cancer cell, and it would make you

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a cancer victim.

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Well, this did not make sense to me.

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Do you even know how a trillion looks?

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Now, let's look at it.

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There it comes, these zeroes after zeroes after zeroes.

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Now, if .0001 of these cells got mutated,

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

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

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Why not?

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So, I decided over the years,

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because of a series of experiments

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that this is because of context and architecture.

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And let me quickly tell you

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some crucial experiment that was able to actually show this.

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To begin with, I came to work with this virus

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that causes that ugly tumor in the chicken.

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Rous discovered this in 1911.

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It was the first cancer virus discovered,

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

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So, he made a filtrate, he took this filter

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

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

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So, scientists were very excited,

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and they said, a single oncogene can do it.

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All you need is a single oncogene.

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

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dumped the virus on it,

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and it would pile up,

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

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And again this didn't make sense to me.

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So for various reasons, we took this oncogene,

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attached it to a blue marker,

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and we injected it into the embryos.

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

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Every one of those blue cells are a cancer gene

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

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

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we got a mass of blue cells.

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So, in the chicken you get a tumor,

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in the embryo you don't,

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

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What does that mean?

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That means that microenvironment

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and the context which surrounds those cells

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

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Now, let's take a normal example.

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

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I work on breast cancer.

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So, here is a lovely human breast.

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And many of you know how it looks,

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except that inside that breast, there are all these

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pretty, developing, tree-like structures.

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So, we decided that what we like to do

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is take just a bit of that mammary gland,

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which is called an "acinus,"

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where there are all these little things inside the breast

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where the milk goes, and the end of the nipple

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comes through that little tube when the baby sucks.

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

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

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how do the cells do that?

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So, we took the red cells --

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you see the red cells are surrounded by blue,

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other cells that squeeze them, and behind it

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is material that people thought was mainly inert,

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

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and so we first photographed it

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with the electron microscope years and years ago,

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and you see this cell is actually quite pretty.

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It has a bottom, it has a top,

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it is secreting gobs and gobs of milk,

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because it just came from an early pregnant mouse.

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

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and within three days, they look like that.

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They completely forget.

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

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they don't make milk. They completely forget.

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For example, here is a lovely yellow droplet of milk

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on the left, there is nothing on the right.

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

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

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They are completely different from each other.

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So, what does this tell you?

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This tells you that here also, context overrides.

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In different contexts, cells do different things.

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But how does context signal?

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So, Einstein said that

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

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So, you can imagine the amount of skepticism

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I received -- couldn't get money,

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couldn't do a whole lot of other things,

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but I'm so glad it all worked out.

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

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and all those lovely acini are there,

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

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

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and I said, maybe that red stuff

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

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maybe it has information,

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

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So I said, extracellular matrix, which is this stuff

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

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

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We found some gooey material

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that had the right extracellular matrix in it,

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

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in about four days, they got reorganized

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

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

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and the one in culture was full of milk,

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the lovely red there is full of milk.

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So, we Got Milk, for the American audience.

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All right. And here is this beautiful human cell,

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and you can imagine that here also, context goes.

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So, what do we do now?

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I made a radical hypothesis.

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

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architecture restored to a cancer cell

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should make the cancer cell think it's normal.

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Could this be done?

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So, we tried it.

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In order to do that, however,

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

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and on the left is the single normal cell,

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human breast, put in three-dimensional gooey gel

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

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On the right, you see it looks very ugly,

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the cells continue to grow,

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the normal ones stop.

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And you see here in higher magnification

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the normal acinus and the ugly tumor.

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

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Could we calm them down --

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

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and make them to the level of the normal?

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Well, it was wonderful. Boggles my mind.

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This is what we got.

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We can revert the malignant phenotype.

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(Applause)

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And in order to show you that the malignant phenotype

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I didn't just choose one,

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here are little movies, sort of fuzzy,

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

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all of them are malignant,

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we add one single inhibitor in the beginning,

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and look what happens, they all look like that.

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

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and none of them would make tumors.

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

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

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it's a hopeful way of thinking about cancer.

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

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and these conclusions say that growth and malignant behavior

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is regulated at the level of tissue organization

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and that the tissue organization is dependent

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on the extracellular matrix and the microenvironment.

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

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And here is another five seconds of repose,

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is my mantra. Form and function.

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

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

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

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

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in your 70 trillion cells,

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the extracellular matrix signaling to your nucleus,

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the nucleus is signaling to your extracellular matrix

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and this is how your balance is kept and restored.

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We have made a lot of discoveries,

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we have shown that extracellular matrix talks to chromatin.

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We have shown that there's little pieces of DNA

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on the specific genes of the mammary gland

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that actually respond to extracellular matrix.

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

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

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that there are so many additional discoveries to be made.

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There is so much mystery we don't know.

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

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don't be arrogant, because arrogance kills curiosity.

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Curiosity and passion.

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

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And maybe my discovery needs to be added to

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or maybe it needs to be changed.

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So, we have now made an amazing discovery,

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

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what do the cells do when you put them in?

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What do they do in the beginning when they do?

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

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

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So she, being an imager and a physicist,

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did this incredible thing.

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This is a single human breast cell in three dimensions.

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Look at it. It's constantly doing this.

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Has a coherent movement.

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

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they do this. They don't do this.

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

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Absolutely boggles my mind.

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

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So I'd like to finish with a poem.

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Well I used to love English literature,

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

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And unfortunately or fortunately, chemistry won.

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

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It's called "Among the School Children."

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"O body swayed to music / O brightening glance /

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

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And here is Merce Cunningham,

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

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and here he is a dancer,

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

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The minute he stops, we have neither.

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So it's like form and function.

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

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I have been fortunate to have had these magnificant

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

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

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

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of being the cat and being told,

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don't think outside the box.

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

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On the left is water coming through the shore,

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taken from a NASA satellite.

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On the right, there is a coral.

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Now if you take the mammary gland and spread it

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

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

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

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And I'd like to submit to you

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that we have sequenced the human genome,

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we know everything about the sequence of the gene,

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

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But we know nothing, but nothing,

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about the language and alphabet of form.

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So, it's a wonderful new horizon,

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it's a wonderful thing to discover for the young

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and the passionate old, and that's me.

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So go to it!

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(Applause)