Experiments that point to a new understanding of cancer
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0:00 - 0:03Now, I don't usually like cartoons,
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0:03 - 0:06I don't think many of them are funny,
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0:06 - 0:11I find them weird. But I love this cartoon from the New Yorker.
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0:11 - 0:13(Text: Never, ever think outside the box.) (Laughter)
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0:13 - 0:16So, the guy is telling the cat,
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0:16 - 0:21don't you dare think outside the box.
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0:21 - 0:25Well, I'm afraid I used to be the cat.
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0:25 - 0:28I always wanted to be outside the box.
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0:28 - 0:31And it's partly because I came to this field
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0:31 - 0:36from a different background, chemist and a bacterial geneticist.
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0:36 - 0:39So, what people were saying to me
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0:39 - 0:42about the cause of cancer, sources of cancer,
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0:42 - 0:45or, for that matter, why you are who you are,
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0:45 - 0:47didn't make sense.
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0:47 - 0:50So, let me quickly try and tell you why I thought that
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0:50 - 0:53and how I went about it.
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0:53 - 0:55So, to begin with, however,
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0:55 - 1:00I have to give you a very, very quick lesson
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1:00 - 1:01in developmental biology,
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1:01 - 1:05with apologies to those of you who know some biology.
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1:05 - 1:08So, when your mom and dad met,
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1:08 - 1:11there is a fertilized egg,
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1:11 - 1:13that round thing with that little blip.
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1:13 - 1:16It grows and then it grows,
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1:16 - 1:20and then it makes this handsome man.
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1:20 - 1:22(Applause)
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1:22 - 1:28So, this guy, with all the cells in his body,
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1:28 - 1:32all have the same genetic information.
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1:32 - 1:36So how did his nose become his nose, his elbow his elbow,
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1:36 - 1:38and why doesn't he get up one morning
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1:38 - 1:41and have his nose turn into his foot?
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1:41 - 1:44It could. It has the genetic information.
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1:44 - 1:45You all remember, dolly,
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1:45 - 1:48it came from a single mammary cell.
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1:48 - 1:50So, why doesn't it do it?
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1:50 - 1:55So, have a guess of how many cells he has in his body.
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1:55 - 2:03Somewhere between 10 trillion to 70 trillion cells in his body.
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2:03 - 2:05Trillion!
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2:05 - 2:09Now, how did these cells, all with the same genetic material,
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2:09 - 2:11make all those tissues?
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2:11 - 2:14And so, the question I raised before
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2:14 - 2:18becomes even more interesting if you thought about
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2:18 - 2:23the enormity of this in every one of your bodies.
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2:23 - 2:26Now, the dominant cancer theory would say
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2:26 - 2:28that there is a single oncogene
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2:28 - 2:32in a single cancer cell, and it would make you
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2:32 - 2:34a cancer victim.
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2:34 - 2:38Well, this did not make sense to me.
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2:38 - 2:41Do you even know how a trillion looks?
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2:41 - 2:43Now, let's look at it.
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2:43 - 2:48There it comes, these zeroes after zeroes after zeroes.
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2:48 - 2:55Now, if .0001 of these cells got mutated,
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2:55 - 3:00and .00001 got cancer, you will be a lump of cancer.
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3:00 - 3:02You will have cancer all over you. And you're not.
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3:02 - 3:05Why not?
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3:05 - 3:08So, I decided over the years,
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3:08 - 3:10because of a series of experiments
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3:10 - 3:15that this is because of context and architecture.
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3:15 - 3:17And let me quickly tell you
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3:17 - 3:21some crucial experiment that was able to actually show this.
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3:21 - 3:25To begin with, I came to work with this virus
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3:25 - 3:29that causes that ugly tumor in the chicken.
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3:29 - 3:32Rous discovered this in 1911.
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3:32 - 3:36It was the first cancer virus discovered,
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3:36 - 3:40and when I call it "oncogene," meaning "cancer gene."
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3:40 - 3:43So, he made a filtrate, he took this filter
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3:43 - 3:48which was the liquid after he passed the tumor through a filter,
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3:48 - 3:52and he injected it to another chicken, and he got another tumor.
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3:52 - 3:54So, scientists were very excited,
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3:54 - 3:56and they said, a single oncogene can do it.
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3:56 - 3:59All you need is a single oncogene.
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3:59 - 4:02So, they put the cells in cultures, chicken cells,
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4:02 - 4:04dumped the virus on it,
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4:04 - 4:05and it would pile up,
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4:05 - 4:08and they would say, this is malignant and this is normal.
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4:08 - 4:10And again this didn't make sense to me.
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4:10 - 4:13So for various reasons, we took this oncogene,
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4:13 - 4:16attached it to a blue marker,
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4:16 - 4:19and we injected it into the embryos.
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4:19 - 4:23Now look at that. There is that beautiful feather in the embryo.
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4:23 - 4:27Every one of those blue cells are a cancer gene
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4:27 - 4:32inside a cancer cell, and they're part of the feather.
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4:32 - 4:36So, when we dissociated the feather and put it in a dish,
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4:36 - 4:39we got a mass of blue cells.
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4:39 - 4:40So, in the chicken you get a tumor,
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4:40 - 4:42in the embryo you don't,
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4:42 - 4:46you dissociate, you put it in a dish, you get another tumor.
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4:46 - 4:47What does that mean?
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4:47 - 4:50That means that microenvironment
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4:50 - 4:54and the context which surrounds those cells
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4:54 - 5:01actually are telling the cancer gene and the cancer cell what to do.
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5:01 - 5:05Now, let's take a normal example.
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5:05 - 5:08The normal example, let's take the human mammary gland.
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5:08 - 5:09I work on breast cancer.
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5:09 - 5:12So, here is a lovely human breast.
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5:12 - 5:14And many of you know how it looks,
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5:14 - 5:17except that inside that breast, there are all these
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5:17 - 5:20pretty, developing, tree-like structures.
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5:20 - 5:23So, we decided that what we like to do
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5:23 - 5:26is take just a bit of that mammary gland,
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5:26 - 5:28which is called an "acinus,"
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5:28 - 5:32where there are all these little things inside the breast
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5:32 - 5:36where the milk goes, and the end of the nipple
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5:36 - 5:39comes through that little tube when the baby sucks.
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5:39 - 5:42And we said, wonderful! Look at this pretty structure.
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5:42 - 5:46We want to make this a structure, and ask the question,
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5:46 - 5:48how do the cells do that?
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5:48 - 5:50So, we took the red cells --
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5:50 - 5:53you see the red cells are surrounded by blue,
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5:53 - 5:56other cells that squeeze them, and behind it
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5:56 - 6:00is material that people thought was mainly inert,
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6:00 - 6:04and it was just having a structure to keep the shape,
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6:04 - 6:07and so we first photographed it
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6:07 - 6:09with the electron microscope years and years ago,
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6:09 - 6:12and you see this cell is actually quite pretty.
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6:12 - 6:15It has a bottom, it has a top,
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6:15 - 6:18it is secreting gobs and gobs of milk,
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6:18 - 6:21because it just came from an early pregnant mouse.
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6:21 - 6:23You take these cells, you put them in a dish,
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6:23 - 6:26and within three days, they look like that.
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6:26 - 6:30They completely forget.
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6:30 - 6:32So you take them out, you put them in a dish,
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6:32 - 6:35they don't make milk. They completely forget.
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6:35 - 6:40For example, here is a lovely yellow droplet of milk
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6:40 - 6:42on the left, there is nothing on the right.
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6:42 - 6:46Look at the nuclei. The nuclei in the cell on the left
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6:46 - 6:49is in the animal, the one on the right is in a dish.
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6:49 - 6:52They are completely different from each other.
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6:52 - 6:54So, what does this tell you?
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6:54 - 6:59This tells you that here also, context overrides.
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6:59 - 7:02In different contexts, cells do different things.
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7:02 - 7:05But how does context signal?
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7:05 - 7:08So, Einstein said that
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7:08 - 7:14"For an idea that does not first seem insane, there is no hope."
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7:14 - 7:20So, you can imagine the amount of skepticism
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7:20 - 7:23I received -- couldn't get money,
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7:23 - 7:25couldn't do a whole lot of other things,
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7:25 - 7:26but I'm so glad it all worked out.
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7:26 - 7:30So, we made a section of the mammary gland of the mouse,
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7:30 - 7:33and all those lovely acini are there,
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7:33 - 7:38every one of those with the red around them are an acinus,
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7:38 - 7:41and we said okay, we are going to try and make this,
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7:41 - 7:45and I said, maybe that red stuff
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7:45 - 7:50around the acinus that people think there's just a structural scaffold,
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7:50 - 7:52maybe it has information,
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7:52 - 7:56maybe it tells the cells what to do, maybe it tells the nucleus what to do.
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7:56 - 8:01So I said, extracellular matrix, which is this stuff
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8:01 - 8:05called ECM, signals and actually tells the cells what to do.
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8:05 - 8:09So, we decided to make things that would look like that.
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8:09 - 8:12We found some gooey material
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8:12 - 8:14that had the right extracellular matrix in it,
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8:14 - 8:17we put the cells in it, and lo and behold,
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8:17 - 8:20in about four days, they got reorganized
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8:20 - 8:23and on the right, is what we can make in culture.
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8:23 - 8:28On the left is what's inside the animal, we call it in vivo,
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8:28 - 8:30and the one in culture was full of milk,
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8:30 - 8:33the lovely red there is full of milk.
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8:33 - 8:36So, we Got Milk, for the American audience.
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8:36 - 8:42All right. And here is this beautiful human cell,
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8:42 - 8:47and you can imagine that here also, context goes.
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8:47 - 8:49So, what do we do now?
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8:49 - 8:52I made a radical hypothesis.
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8:52 - 8:58I said, if it's true that architecture is dominant,
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8:58 - 9:03architecture restored to a cancer cell
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9:03 - 9:06should make the cancer cell think it's normal.
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9:06 - 9:07Could this be done?
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9:07 - 9:10So, we tried it.
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9:10 - 9:12In order to do that, however,
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9:12 - 9:17we needed to have a method of distinguishing normal from malignant,
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9:17 - 9:21and on the left is the single normal cell,
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9:21 - 9:25human breast, put in three-dimensional gooey gel
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9:25 - 9:29that has extracellular matrix, it makes all these beautiful structures.
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9:29 - 9:32On the right, you see it looks very ugly,
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9:32 - 9:33the cells continue to grow,
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9:33 - 9:35the normal ones stop.
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9:35 - 9:38And you see here in higher magnification
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9:38 - 9:42the normal acinus and the ugly tumor.
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9:42 - 9:46So we said, what is on the surface of these ugly tumors?
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9:46 - 9:48Could we calm them down --
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9:48 - 9:53they were signaling like crazy and they have pathways all messed up --
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9:53 - 9:56and make them to the level of the normal?
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9:56 - 10:01Well, it was wonderful. Boggles my mind.
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10:01 - 10:03This is what we got.
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10:03 - 10:07We can revert the malignant phenotype.
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10:07 - 10:09(Applause)
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10:09 - 10:13And in order to show you that the malignant phenotype
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10:13 - 10:14I didn't just choose one,
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10:14 - 10:17here are little movies, sort of fuzzy,
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10:17 - 10:21but you see that on the left are the malignant cells,
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10:21 - 10:22all of them are malignant,
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10:22 - 10:27we add one single inhibitor in the beginning,
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10:27 - 10:30and look what happens, they all look like that.
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10:30 - 10:34We inject them into the mouse, the ones on the right,
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10:34 - 10:36and none of them would make tumors.
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10:36 - 10:39We inject the other ones in the mouse, 100 percent tumors.
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10:39 - 10:42So, it's a new way of thinking about cancer,
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10:42 - 10:45it's a hopeful way of thinking about cancer.
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10:45 - 10:49We should be able to be dealing with these things at this level,
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10:49 - 10:54and these conclusions say that growth and malignant behavior
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10:54 - 10:58is regulated at the level of tissue organization
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10:58 - 11:02and that the tissue organization is dependent
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11:02 - 11:06on the extracellular matrix and the microenvironment.
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11:06 - 11:14All right, thus form and function interact dynamically and reciprocally.
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11:14 - 11:18And here is another five seconds of repose,
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11:18 - 11:22is my mantra. Form and function.
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11:22 - 11:26And of course, we now ask, where do we go now?
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11:26 - 11:29We'd like to take this kind of thinking into the clinic.
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11:29 - 11:33But before we do that, I'd like you to think
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11:33 - 11:36that at any given time when you're sitting there,
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11:36 - 11:39in your 70 trillion cells,
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11:39 - 11:43the extracellular matrix signaling to your nucleus,
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11:43 - 11:46the nucleus is signaling to your extracellular matrix
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11:46 - 11:52and this is how your balance is kept and restored.
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11:52 - 11:54We have made a lot of discoveries,
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11:54 - 11:57we have shown that extracellular matrix talks to chromatin.
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11:57 - 12:01We have shown that there's little pieces of DNA
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12:01 - 12:04on the specific genes of the mammary gland
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12:04 - 12:07that actually respond to extracellular matrix.
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12:07 - 12:11It has taken many years, but it has been very rewarding.
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12:11 - 12:15And before I get to the next slide, I have to tell you
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12:15 - 12:21that there are so many additional discoveries to be made.
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12:21 - 12:23There is so much mystery we don't know.
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12:23 - 12:27And I always say to the students and post-docs I lecture to,
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12:27 - 12:33don't be arrogant, because arrogance kills curiosity.
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12:33 - 12:35Curiosity and passion.
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12:35 - 12:39You need to always think, what else needs to be discovered?
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12:39 - 12:42And maybe my discovery needs to be added to
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12:42 - 12:44or maybe it needs to be changed.
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12:44 - 12:47So, we have now made an amazing discovery,
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12:47 - 12:51a post-doc in the lab who is a physicist asked me,
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12:51 - 12:53what do the cells do when you put them in?
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12:53 - 12:56What do they do in the beginning when they do?
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12:56 - 12:58I said, I don't know, we couldn't look at them.
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12:58 - 13:00We didn't have high images in the old days.
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13:00 - 13:03So she, being an imager and a physicist,
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13:03 - 13:05did this incredible thing.
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13:05 - 13:09This is a single human breast cell in three dimensions.
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13:09 - 13:11Look at it. It's constantly doing this.
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13:11 - 13:14Has a coherent movement.
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13:14 - 13:18You put the cancer cells there, and they do go all over,
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13:18 - 13:20they do this. They don't do this.
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13:20 - 13:24And when we revert the cancer cell, it again does this.
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13:24 - 13:26Absolutely boggles my mind.
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13:26 - 13:31So the cell acts like an embryo. What an exciting thing.
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13:31 - 13:34So I'd like to finish with a poem.
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13:34 - 13:37Well I used to love English literature,
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13:37 - 13:40and I debated in college, which one should I do?
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13:40 - 13:44And unfortunately or fortunately, chemistry won.
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13:44 - 13:50But here is a poem from Yeats. I'll just read you the last two lines.
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13:50 - 13:53It's called "Among the School Children."
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13:53 - 13:57"O body swayed to music / O brightening glance /
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13:57 - 14:01How [can we know] the dancer from the dance?"
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14:01 - 14:02And here is Merce Cunningham,
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14:02 - 14:05I was fortunate to dance with him when I was younger,
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14:05 - 14:08and here he is a dancer,
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14:08 - 14:11and while he is dancing, he is both the dancer and the dance.
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14:11 - 14:15The minute he stops, we have neither.
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14:15 - 14:18So it's like form and function.
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14:18 - 14:24Now, I'd like to show you a current picture of my group.
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14:24 - 14:27I have been fortunate to have had these magnificant
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14:27 - 14:31students and post-docs who have taught me so much,
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14:31 - 14:34and I have had many of these groups come and go.
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14:34 - 14:38They are the future and I try to make them not be afraid
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14:38 - 14:42of being the cat and being told,
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14:42 - 14:44don't think outside the box.
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14:44 - 14:46And I'd like to leave you with this thought.
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14:46 - 14:51On the left is water coming through the shore,
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14:51 - 14:53taken from a NASA satellite.
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14:53 - 14:56On the right, there is a coral.
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14:56 - 15:00Now if you take the mammary gland and spread it
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15:00 - 15:03and take the fat away, on a dish it looks like that.
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15:03 - 15:07Do they look the same? Do they have the same patterns?
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15:07 - 15:11Why is it that nature keeps doing that over and over again?
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15:11 - 15:13And I'd like to submit to you
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15:13 - 15:15that we have sequenced the human genome,
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15:15 - 15:18we know everything about the sequence of the gene,
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15:18 - 15:21the language of the gene, the alphabet of the gene,
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15:21 - 15:24But we know nothing, but nothing,
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15:24 - 15:28about the language and alphabet of form.
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15:28 - 15:31So, it's a wonderful new horizon,
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15:31 - 15:35it's a wonderful thing to discover for the young
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15:35 - 15:38and the passionate old, and that's me.
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15:38 - 15:40So go to it!
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15:40 - 15:51(Applause)
- Title:
- Experiments that point to a new understanding of cancer
- Speaker:
- Mina Bissell
- Description:
-
For decades, researcher Mina Bissell pursued a revolutionary idea -- that a cancer cell doesn't automatically become a tumor, but rather, depends on surrounding cells (its microenvironment) for cues on how to develop. She shares the two key experiments that proved the prevailing wisdom about cancer growth was wrong.
- Video Language:
- English
- Team:
- closed TED
- Project:
- TEDTalks
- Duration:
- 16:18
Thu-Huong Ha edited English subtitles for Experiments that point to a new understanding of cancer | ||
Thu-Huong Ha approved English subtitles for Experiments that point to a new understanding of cancer | ||
Thu-Huong Ha accepted English subtitles for Experiments that point to a new understanding of cancer | ||
Thu-Huong Ha edited English subtitles for Experiments that point to a new understanding of cancer | ||
Morton Bast edited English subtitles for Experiments that point to a new understanding of cancer | ||
Morton Bast added a translation |