00:11 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.
00:21 (Text: Never, ever think outside the box.) (Laughter)
00:24 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.
00:58 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.
01:32 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.
02:33 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?
03:15 So, I decided over the years, because of a series of experiments that this is because of context and architecture.
03:26 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.
04:02 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.
04:19 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.
05:12 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.
05:50 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.
06:31 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.
07:03 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.
07:37 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.
08:15 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.
08:57 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.
09:52 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.
10:20 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.
10:50 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.
11:33 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.
12:02 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.
12:22 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.
12:54 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.
13:42 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.
14:29 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.
14:54 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?
15:21 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.
15:48 So go to it!