0:00:00.432,0:00:03.154 Now, I don't usually like cartoons, 0:00:03.154,0:00:05.664 I don't think many of them are funny, 0:00:05.664,0:00:10.887 I find them weird. But I love this cartoon from the New Yorker. 0:00:10.887,0:00:13.499 (Text: Never, ever think outside the box.) (Laughter) 0:00:13.499,0:00:15.968 So, the guy is telling the cat, 0:00:15.968,0:00:21.339 don't you dare think outside the box. 0:00:21.339,0:00:24.646 Well, I'm afraid I used to be the cat. 0:00:24.646,0:00:27.704 I always wanted to be outside the box. 0:00:27.704,0:00:31.186 And it's partly because I came to this field 0:00:31.186,0:00:36.399 from a different background, chemist and a bacterial geneticist. 0:00:36.399,0:00:39.001 So, what people were saying to me 0:00:39.001,0:00:42.192 about the cause of cancer, sources of cancer, 0:00:42.192,0:00:45.273 or, for that matter, why you are who you are, 0:00:45.273,0:00:47.147 didn't make sense. 0:00:47.147,0:00:50.194 So, let me quickly try and tell you why I thought that 0:00:50.194,0:00:52.795 and how I went about it. 0:00:52.795,0:00:55.227 So, to begin with, however, 0:00:55.227,0:00:59.653 I have to give you a very, very quick lesson 0:00:59.653,0:01:01.420 in developmental biology, 0:01:01.420,0:01:05.482 with apologies to those of you who know some biology. 0:01:05.482,0:01:08.496 So, when your mom and dad met, 0:01:08.496,0:01:11.170 there is a fertilized egg, 0:01:11.170,0:01:13.291 that round thing with that little blip. 0:01:13.291,0:01:16.346 It grows and then it grows, 0:01:16.346,0:01:20.499 and then it makes this handsome man. 0:01:20.499,0:01:21.914 (Applause) 0:01:21.914,0:01:27.572 So, this guy, with all the cells in his body, 0:01:27.572,0:01:31.784 all have the same genetic information. 0:01:31.784,0:01:36.159 So how did his nose become his nose, his elbow his elbow, 0:01:36.159,0:01:38.335 and why doesn't he get up one morning 0:01:38.335,0:01:40.895 and have his nose turn into his foot? 0:01:40.895,0:01:44.135 It could. It has the genetic information. 0:01:44.135,0:01:45.343 You all remember, dolly, 0:01:45.343,0:01:48.024 it came from a single mammary cell. 0:01:48.024,0:01:49.958 So, why doesn't it do it? 0:01:49.958,0:01:55.461 So, have a guess of how many cells he has in his body. 0:01:55.461,0:02:02.863 Somewhere between 10 trillion to 70 trillion cells in his body. 0:02:02.863,0:02:04.503 Trillion! 0:02:04.503,0:02:09.141 Now, how did these cells, all with the same genetic material, 0:02:09.141,0:02:11.349 make all those tissues? 0:02:11.349,0:02:14.493 And so, the question I raised before 0:02:14.493,0:02:18.107 becomes even more interesting if you thought about 0:02:18.107,0:02:22.693 the enormity of this in every one of your bodies. 0:02:22.693,0:02:25.693 Now, the dominant cancer theory would say 0:02:25.693,0:02:28.005 that there is a single oncogene 0:02:28.005,0:02:31.709 in a single cancer cell, and it would make you 0:02:31.709,0:02:34.358 a cancer victim. 0:02:34.358,0:02:38.024 Well, this did not make sense to me. 0:02:38.024,0:02:41.206 Do you even know how a trillion looks? 0:02:41.206,0:02:42.925 Now, let's look at it. 0:02:42.925,0:02:47.966 There it comes, these zeroes after zeroes after zeroes. 0:02:47.966,0:02:54.784 Now, if .0001 of these cells got mutated, 0:02:54.784,0:03:00.041 and .00001 got cancer, you will be a lump of cancer. 0:03:00.041,0:03:02.337 You will have cancer all over you. And you're not. 0:03:02.337,0:03:04.646 Why not? 0:03:04.646,0:03:08.368 So, I decided over the years, 0:03:08.368,0:03:10.296 because of a series of experiments 0:03:10.296,0:03:15.176 that this is because of context and architecture. 0:03:15.176,0:03:17.353 And let me quickly tell you 0:03:17.353,0:03:21.280 some crucial experiment that was able to actually show this. 0:03:21.280,0:03:25.191 To begin with, I came to work with this virus 0:03:25.191,0:03:28.584 that causes that ugly tumor in the chicken. 0:03:28.584,0:03:31.944 Rous discovered this in 1911. 0:03:31.944,0:03:35.509 It was the first cancer virus discovered, 0:03:35.509,0:03:40.400 and when I call it "oncogene," meaning "cancer gene." 0:03:40.400,0:03:43.312 So, he made a filtrate, he took this filter 0:03:43.312,0:03:47.568 which was the liquid after he passed the tumor through a filter, 0:03:47.568,0:03:51.569 and he injected it to another chicken, and he got another tumor. 0:03:51.569,0:03:54.280 So, scientists were very excited, 0:03:54.280,0:03:56.448 and they said, a single oncogene can do it. 0:03:56.448,0:03:58.744 All you need is a single oncogene. 0:03:58.744,0:04:01.639 So, they put the cells in cultures, chicken cells, 0:04:01.639,0:04:03.674 dumped the virus on it, 0:04:03.674,0:04:05.123 and it would pile up, 0:04:05.123,0:04:08.144 and they would say, this is malignant and this is normal. 0:04:08.144,0:04:10.162 And again this didn't make sense to me. 0:04:10.162,0:04:13.448 So for various reasons, we took this oncogene, 0:04:13.448,0:04:15.760 attached it to a blue marker, 0:04:15.760,0:04:18.768 and we injected it into the embryos. 0:04:18.768,0:04:22.961 Now look at that. There is that beautiful feather in the embryo. 0:04:22.961,0:04:27.240 Every one of those blue cells are a cancer gene 0:04:27.240,0:04:31.656 inside a cancer cell, and they're part of the feather. 0:04:31.656,0:04:36.256 So, when we dissociated the feather and put it in a dish, 0:04:36.256,0:04:38.968 we got a mass of blue cells. 0:04:38.968,0:04:40.434 So, in the chicken you get a tumor, 0:04:40.434,0:04:42.138 in the embryo you don't, 0:04:42.138,0:04:46.130 you dissociate, you put it in a dish, you get another tumor. 0:04:46.130,0:04:47.353 What does that mean? 0:04:47.353,0:04:50.337 That means that microenvironment 0:04:50.337,0:04:54.346 and the context which surrounds those cells 0:04:54.346,0:05:01.273 actually are telling the cancer gene and the cancer cell what to do. 0:05:01.273,0:05:04.585 Now, let's take a normal example. 0:05:04.585,0:05:07.770 The normal example, let's take the human mammary gland. 0:05:07.770,0:05:09.250 I work on breast cancer. 0:05:09.250,0:05:12.257 So, here is a lovely human breast. 0:05:12.257,0:05:14.205 And many of you know how it looks, 0:05:14.205,0:05:17.058 except that inside that breast, there are all these 0:05:17.058,0:05:20.435 pretty, developing, tree-like structures. 0:05:20.435,0:05:23.333 So, we decided that what we like to do 0:05:23.333,0:05:26.293 is take just a bit of that mammary gland, 0:05:26.293,0:05:28.325 which is called an "acinus," 0:05:28.325,0:05:31.966 where there are all these little things inside the breast 0:05:31.966,0:05:35.509 where the milk goes, and the end of the nipple 0:05:35.509,0:05:39.053 comes through that little tube when the baby sucks. 0:05:39.053,0:05:42.460 And we said, wonderful! Look at this pretty structure. 0:05:42.460,0:05:46.229 We want to make this a structure, and ask the question, 0:05:46.229,0:05:47.933 how do the cells do that? 0:05:47.933,0:05:49.725 So, we took the red cells -- 0:05:49.725,0:05:52.973 you see the red cells are surrounded by blue, 0:05:52.973,0:05:56.302 other cells that squeeze them, and behind it 0:05:56.302,0:06:00.020 is material that people thought was mainly inert, 0:06:00.020,0:06:03.617 and it was just having a structure to keep the shape, 0:06:03.617,0:06:06.545 and so we first photographed it 0:06:06.545,0:06:09.313 with the electron microscope years and years ago, 0:06:09.313,0:06:12.369 and you see this cell is actually quite pretty. 0:06:12.369,0:06:14.832 It has a bottom, it has a top, 0:06:14.832,0:06:17.513 it is secreting gobs and gobs of milk, 0:06:17.513,0:06:20.705 because it just came from an early pregnant mouse. 0:06:20.705,0:06:23.032 You take these cells, you put them in a dish, 0:06:23.032,0:06:26.377 and within three days, they look like that. 0:06:26.377,0:06:29.537 They completely forget. 0:06:29.537,0:06:32.337 So you take them out, you put them in a dish, 0:06:32.337,0:06:35.000 they don't make milk. They completely forget. 0:06:35.000,0:06:39.899 For example, here is a lovely yellow droplet of milk 0:06:39.899,0:06:42.154 on the left, there is nothing on the right. 0:06:42.154,0:06:45.883 Look at the nuclei. The nuclei in the cell on the left 0:06:45.883,0:06:49.379 is in the animal, the one on the right is in a dish. 0:06:49.379,0:06:52.115 They are completely different from each other. 0:06:52.115,0:06:54.140 So, what does this tell you? 0:06:54.140,0:06:59.107 This tells you that here also, context overrides. 0:06:59.107,0:07:02.492 In different contexts, cells do different things. 0:07:02.492,0:07:05.237 But how does context signal? 0:07:05.237,0:07:07.779 So, Einstein said that 0:07:07.779,0:07:14.432 "For an idea that does not first seem insane, there is no hope." 0:07:14.432,0:07:20.392 So, you can imagine the amount of skepticism 0:07:20.392,0:07:22.793 I received -- couldn't get money, 0:07:22.793,0:07:24.736 couldn't do a whole lot of other things, 0:07:24.736,0:07:26.465 but I'm so glad it all worked out. 0:07:26.465,0:07:30.280 So, we made a section of the mammary gland of the mouse, 0:07:30.280,0:07:33.463 and all those lovely acini are there, 0:07:33.463,0:07:37.674 every one of those with the red around them are an acinus, 0:07:37.674,0:07:41.368 and we said okay, we are going to try and make this, 0:07:41.368,0:07:44.600 and I said, maybe that red stuff 0:07:44.600,0:07:49.725 around the acinus that people think there's just a structural scaffold, 0:07:49.725,0:07:51.665 maybe it has information, 0:07:51.665,0:07:56.231 maybe it tells the cells what to do, maybe it tells the nucleus what to do. 0:07:56.231,0:08:00.514 So I said, extracellular matrix, which is this stuff 0:08:00.514,0:08:04.905 called ECM, signals and actually tells the cells what to do. 0:08:04.905,0:08:08.672 So, we decided to make things that would look like that. 0:08:08.672,0:08:11.552 We found some gooey material 0:08:11.552,0:08:14.427 that had the right extracellular matrix in it, 0:08:14.427,0:08:16.966 we put the cells in it, and lo and behold, 0:08:16.966,0:08:19.787 in about four days, they got reorganized 0:08:19.787,0:08:23.195 and on the right, is what we can make in culture. 0:08:23.195,0:08:27.691 On the left is what's inside the animal, we call it in vivo, 0:08:27.691,0:08:30.275 and the one in culture was full of milk, 0:08:30.275,0:08:33.075 the lovely red there is full of milk. 0:08:33.075,0:08:36.491 So, we Got Milk, for the American audience. 0:08:36.491,0:08:41.835 All right. And here is this beautiful human cell, 0:08:41.835,0:08:46.781 and you can imagine that here also, context goes. 0:08:46.781,0:08:49.497 So, what do we do now? 0:08:49.497,0:08:51.721 I made a radical hypothesis. 0:08:51.721,0:08:58.384 I said, if it's true that architecture is dominant, 0:08:58.384,0:09:02.870 architecture restored to a cancer cell 0:09:02.870,0:09:05.859 should make the cancer cell think it's normal. 0:09:05.859,0:09:07.343 Could this be done? 0:09:07.343,0:09:09.871 So, we tried it. 0:09:09.871,0:09:11.909 In order to do that, however, 0:09:11.909,0:09:16.794 we needed to have a method of distinguishing normal from malignant, 0:09:16.794,0:09:20.791 and on the left is the single normal cell, 0:09:20.791,0:09:24.754 human breast, put in three-dimensional gooey gel 0:09:24.754,0:09:28.618 that has extracellular matrix, it makes all these beautiful structures. 0:09:28.618,0:09:31.506 On the right, you see it looks very ugly, 0:09:31.506,0:09:33.154 the cells continue to grow, 0:09:33.154,0:09:34.730 the normal ones stop. 0:09:34.730,0:09:37.562 And you see here in higher magnification 0:09:37.562,0:09:41.914 the normal acinus and the ugly tumor. 0:09:41.914,0:09:46.138 So we said, what is on the surface of these ugly tumors? 0:09:46.138,0:09:48.306 Could we calm them down -- 0:09:48.306,0:09:53.226 they were signaling like crazy and they have pathways all messed up -- 0:09:53.226,0:09:56.290 and make them to the level of the normal? 0:09:56.290,0:10:01.010 Well, it was wonderful. Boggles my mind. 0:10:01.010,0:10:03.171 This is what we got. 0:10:03.171,0:10:06.850 We can revert the malignant phenotype. 0:10:06.850,0:10:09.418 (Applause) 0:10:09.418,0:10:12.530 And in order to show you that the malignant phenotype 0:10:12.530,0:10:14.248 I didn't just choose one, 0:10:14.248,0:10:17.018 here are little movies, sort of fuzzy, 0:10:17.018,0:10:20.674 but you see that on the left are the malignant cells, 0:10:20.674,0:10:22.018 all of them are malignant, 0:10:22.018,0:10:26.818 we add one single inhibitor in the beginning, 0:10:26.818,0:10:30.275 and look what happens, they all look like that. 0:10:30.275,0:10:33.722 We inject them into the mouse, the ones on the right, 0:10:33.722,0:10:35.962 and none of them would make tumors. 0:10:35.962,0:10:39.498 We inject the other ones in the mouse, 100 percent tumors. 0:10:39.498,0:10:42.170 So, it's a new way of thinking about cancer, 0:10:42.170,0:10:44.570 it's a hopeful way of thinking about cancer. 0:10:44.570,0:10:48.546 We should be able to be dealing with these things at this level, 0:10:48.546,0:10:54.458 and these conclusions say that growth and malignant behavior 0:10:54.458,0:10:58.330 is regulated at the level of tissue organization 0:10:58.330,0:11:02.322 and that the tissue organization is dependent 0:11:02.322,0:11:06.018 on the extracellular matrix and the microenvironment. 0:11:06.018,0:11:13.649 All right, thus form and function interact dynamically and reciprocally. 0:11:13.649,0:11:17.769 And here is another five seconds of repose, 0:11:17.769,0:11:22.191 is my mantra. Form and function. 0:11:22.191,0:11:25.837 And of course, we now ask, where do we go now? 0:11:25.837,0:11:28.832 We'd like to take this kind of thinking into the clinic. 0:11:28.832,0:11:32.756 But before we do that, I'd like you to think 0:11:32.756,0:11:36.344 that at any given time when you're sitting there, 0:11:36.344,0:11:39.357 in your 70 trillion cells, 0:11:39.357,0:11:42.830 the extracellular matrix signaling to your nucleus, 0:11:42.830,0:11:45.908 the nucleus is signaling to your extracellular matrix 0:11:45.908,0:11:51.902 and this is how your balance is kept and restored. 0:11:51.902,0:11:54.117 We have made a lot of discoveries, 0:11:54.117,0:11:57.205 we have shown that extracellular matrix talks to chromatin. 0:11:57.205,0:12:00.652 We have shown that there's little pieces of DNA 0:12:00.652,0:12:04.475 on the specific genes of the mammary gland 0:12:04.475,0:12:07.339 that actually respond to extracellular matrix. 0:12:07.339,0:12:11.036 It has taken many years, but it has been very rewarding. 0:12:11.036,0:12:15.427 And before I get to the next slide, I have to tell you 0:12:15.427,0:12:20.539 that there are so many additional discoveries to be made. 0:12:20.539,0:12:23.067 There is so much mystery we don't know. 0:12:23.067,0:12:27.428 And I always say to the students and post-docs I lecture to, 0:12:27.428,0:12:33.091 don't be arrogant, because arrogance kills curiosity. 0:12:33.091,0:12:35.283 Curiosity and passion. 0:12:35.283,0:12:39.180 You need to always think, what else needs to be discovered? 0:12:39.180,0:12:42.155 And maybe my discovery needs to be added to 0:12:42.155,0:12:43.947 or maybe it needs to be changed. 0:12:43.947,0:12:47.451 So, we have now made an amazing discovery, 0:12:47.451,0:12:50.555 a post-doc in the lab who is a physicist asked me, 0:12:50.555,0:12:52.732 what do the cells do when you put them in? 0:12:52.732,0:12:56.026 What do they do in the beginning when they do? 0:12:56.026,0:12:57.507 I said, I don't know, we couldn't look at them. 0:12:57.507,0:13:00.100 We didn't have high images in the old days. 0:13:00.100,0:13:02.795 So she, being an imager and a physicist, 0:13:02.795,0:13:04.539 did this incredible thing. 0:13:04.539,0:13:08.915 This is a single human breast cell in three dimensions. 0:13:08.915,0:13:11.443 Look at it. It's constantly doing this. 0:13:11.443,0:13:13.539 Has a coherent movement. 0:13:13.539,0:13:17.873 You put the cancer cells there, and they do go all over, 0:13:17.873,0:13:19.777 they do this. They don't do this. 0:13:19.777,0:13:23.785 And when we revert the cancer cell, it again does this. 0:13:23.785,0:13:25.969 Absolutely boggles my mind. 0:13:25.969,0:13:31.313 So the cell acts like an embryo. What an exciting thing. 0:13:31.313,0:13:34.169 So I'd like to finish with a poem. 0:13:34.169,0:13:37.233 Well I used to love English literature, 0:13:37.233,0:13:39.840 and I debated in college, which one should I do? 0:13:39.840,0:13:44.452 And unfortunately or fortunately, chemistry won. 0:13:44.452,0:13:50.176 But here is a poem from Yeats. I'll just read you the last two lines. 0:13:50.176,0:13:52.835 It's called "Among the School Children." 0:13:52.835,0:13:57.356 "O body swayed to music / O brightening glance / 0:13:57.356,0:14:00.506 How [can we know] the dancer from the dance?" 0:14:00.506,0:14:02.417 And here is Merce Cunningham, 0:14:02.417,0:14:05.401 I was fortunate to dance with him when I was younger, 0:14:05.401,0:14:07.594 and here he is a dancer, 0:14:07.594,0:14:10.898 and while he is dancing, he is both the dancer and the dance. 0:14:10.898,0:14:14.599 The minute he stops, we have neither. 0:14:14.599,0:14:18.073 So it's like form and function. 0:14:18.073,0:14:23.852 Now, I'd like to show you a current picture of my group. 0:14:23.852,0:14:27.380 I have been fortunate to have had these magnificant 0:14:27.380,0:14:30.604 students and post-docs who have taught me so much, 0:14:30.604,0:14:33.867 and I have had many of these groups come and go. 0:14:33.867,0:14:38.444 They are the future and I try to make them not be afraid 0:14:38.444,0:14:42.147 of being the cat and being told, 0:14:42.147,0:14:43.740 don't think outside the box. 0:14:43.740,0:14:46.235 And I'd like to leave you with this thought. 0:14:46.235,0:14:50.980 On the left is water coming through the shore, 0:14:50.980,0:14:52.875 taken from a NASA satellite. 0:14:52.875,0:14:55.924 On the right, there is a coral. 0:14:55.924,0:14:59.926 Now if you take the mammary gland and spread it 0:14:59.926,0:15:03.371 and take the fat away, on a dish it looks like that. 0:15:03.371,0:15:06.723 Do they look the same? Do they have the same patterns? 0:15:06.723,0:15:10.675 Why is it that nature keeps doing that over and over again? 0:15:10.675,0:15:13.035 And I'd like to submit to you 0:15:13.035,0:15:15.212 that we have sequenced the human genome, 0:15:15.212,0:15:18.092 we know everything about the sequence of the gene, 0:15:18.092,0:15:20.523 the language of the gene, the alphabet of the gene, 0:15:20.523,0:15:23.762 But we know nothing, but nothing, 0:15:23.762,0:15:28.425 about the language and alphabet of form. 0:15:28.425,0:15:31.469 So, it's a wonderful new horizon, 0:15:31.469,0:15:35.219 it's a wonderful thing to discover for the young 0:15:35.219,0:15:37.699 and the passionate old, and that's me. 0:15:37.699,0:15:39.747 So go to it! 0:15:39.747,0:15:51.247 (Applause)