1 00:00:00,090 --> 00:00:02,490 The following content is provided under a Creative 2 00:00:02,490 --> 00:00:04,059 Commons license. 3 00:00:04,059 --> 00:00:06,330 Your support will help MIT OpenCourseWare 4 00:00:06,330 --> 00:00:10,720 continue to offer high quality, educational resources for free. 5 00:00:10,720 --> 00:00:13,320 To make a donation, or view additional materials 6 00:00:13,320 --> 00:00:17,280 from hundreds of MIT courses, visit MIT OpenCourseWare 7 00:00:17,280 --> 00:00:18,450 at ocw.mit.edu. 8 00:00:26,980 --> 00:00:29,560 PROFESSOR: The thing we have to talk about here 9 00:00:29,560 --> 00:00:32,619 is multicellular life. 10 00:00:32,619 --> 00:00:36,820 Cells, although we can think of them as entities, 11 00:00:36,820 --> 00:00:40,390 are generally not the unit of a whole organism. 12 00:00:40,390 --> 00:00:44,290 There are many organisms whose unit is a single cell, 13 00:00:44,290 --> 00:00:47,380 but the really interesting ones are the ones 14 00:00:47,380 --> 00:00:49,990 that have got lots of cells. 15 00:00:49,990 --> 00:00:52,630 And so life has developed in a way 16 00:00:52,630 --> 00:00:56,110 that most organisms are multicellular. 17 00:01:06,670 --> 00:01:11,190 And we can pose the question of why that might be. 18 00:01:11,190 --> 00:01:14,580 My trite phrase, while it's more interesting, 19 00:01:14,580 --> 00:01:16,680 is actually a very poor answer. 20 00:01:16,680 --> 00:01:18,630 There's a much better answer. 21 00:01:18,630 --> 00:01:20,400 And that is if you have something 22 00:01:20,400 --> 00:01:24,630 made of lots of cells, different parts of that organism 23 00:01:24,630 --> 00:01:27,220 can specialize and do different things. 24 00:01:27,220 --> 00:01:30,040 And so you can get a diversification of function, 25 00:01:30,040 --> 00:01:32,460 which allows the organism to colonize 26 00:01:32,460 --> 00:01:35,880 new parts of the earth, interact with its environment 27 00:01:35,880 --> 00:01:39,510 in different ways, interact with other members of its species 28 00:01:39,510 --> 00:01:42,060 in different ways, and it does become-- 29 00:01:42,060 --> 00:01:45,090 allow a much greater complexity of life. 30 00:01:45,090 --> 00:01:46,890 So I would say-- the answer I would 31 00:01:46,890 --> 00:01:56,800 give you is it allows new functions to evolve 32 00:01:56,800 --> 00:02:00,750 and greater complexity of life to develop. 33 00:02:06,010 --> 00:02:14,160 If we consider the human adult, and look and see 34 00:02:14,160 --> 00:02:20,630 what we're made of, we contain about 400 different kinds 35 00:02:20,630 --> 00:02:23,620 of cells. 36 00:02:23,620 --> 00:02:33,220 We can call those cell types where each cell type 37 00:02:33,220 --> 00:02:34,630 has a specialized function. 38 00:02:45,030 --> 00:02:49,710 Those cells are organized together, 39 00:02:49,710 --> 00:02:52,080 and they're located in specific places. 40 00:02:54,590 --> 00:03:03,205 So the cell types are organized into groups. 41 00:03:06,680 --> 00:03:09,820 They are organized into three dimensional structures. 42 00:03:09,820 --> 00:03:13,300 One of the things that is most interesting about living 43 00:03:13,300 --> 00:03:17,090 organisms is that they're 3D. 44 00:03:17,090 --> 00:03:19,866 Think of it if we were all sitting there as flat sheets, 45 00:03:19,866 --> 00:03:20,990 you know, you get the idea. 46 00:03:20,990 --> 00:03:24,500 The 3D-ness is extraordinary. 47 00:03:24,500 --> 00:03:27,520 And it's one of the things that being multicellular 48 00:03:27,520 --> 00:03:29,060 allows you to do. 49 00:03:29,060 --> 00:03:31,490 So cells are organized into groups, 50 00:03:31,490 --> 00:03:39,220 they are organized into 3D structures, 51 00:03:39,220 --> 00:03:43,660 and this notion of groups of cells and structures 52 00:03:43,660 --> 00:03:45,700 is that they work together. 53 00:03:45,700 --> 00:03:48,620 Groups of cells arranged in a certain way work 54 00:03:48,620 --> 00:03:53,020 together to form a whole, an organ, 55 00:03:53,020 --> 00:03:57,880 that has got an even greater specialized function. 56 00:03:57,880 --> 00:04:08,580 So these work together to make organs. 57 00:04:08,580 --> 00:04:12,180 And in particular, as we'll talk about next time, 58 00:04:12,180 --> 00:04:15,270 it's the groups of cells and their 3D structures 59 00:04:15,270 --> 00:04:17,220 which makes the organs. 60 00:04:17,220 --> 00:04:22,079 And the organs themselves can be organized into super structures 61 00:04:22,079 --> 00:04:23,455 called organ systems. 62 00:04:27,700 --> 00:04:30,040 And we'll work on all of these things 63 00:04:30,040 --> 00:04:33,730 over the next couple of lectures. 64 00:04:33,730 --> 00:04:37,870 Today we're going to talk about cell type. 65 00:05:01,830 --> 00:05:08,030 Here is-- before-- 66 00:05:08,030 --> 00:05:10,030 I'm thinking if I should show you a slide first, 67 00:05:10,030 --> 00:05:11,370 or if I should write this on the board. 68 00:05:11,370 --> 00:05:14,050 Let me show you a slide first because I want these next two 69 00:05:14,050 --> 00:05:17,500 boards to follow one from another. 70 00:05:17,500 --> 00:05:20,270 All right. 71 00:05:20,270 --> 00:05:23,460 Different cells. 72 00:05:23,460 --> 00:05:23,970 Oh! 73 00:05:23,970 --> 00:05:24,720 There we go, OK. 74 00:05:27,860 --> 00:05:29,690 Different cell types. 75 00:05:29,690 --> 00:05:32,270 These are micrographs of different cell types. 76 00:05:32,270 --> 00:05:35,930 Here are red blood cells, which regulate oxygen transports 77 00:05:35,930 --> 00:05:38,810 for metazoa involved in reproduction, 78 00:05:38,810 --> 00:05:41,600 and neurons involved in communication. 79 00:05:41,600 --> 00:05:44,900 Each of them has got the basic cellular functions 80 00:05:44,900 --> 00:05:48,320 that we've talked about over the last lectures, but each of them 81 00:05:48,320 --> 00:05:50,510 is obviously morphologically different. 82 00:05:50,510 --> 00:05:55,810 They look different and they carry out different functions. 83 00:05:55,810 --> 00:05:58,950 The cell types get organized in specific ways. 84 00:05:58,950 --> 00:06:01,240 This is a really extraordinary example, 85 00:06:01,240 --> 00:06:03,780 which is the retina of your eye, the light sensitive part 86 00:06:03,780 --> 00:06:07,560 of your eye, which contains a number of different kinds 87 00:06:07,560 --> 00:06:08,880 of cells. 88 00:06:08,880 --> 00:06:11,790 And these cells are organized in layers, 89 00:06:11,790 --> 00:06:13,490 and so they're color coded here. 90 00:06:13,490 --> 00:06:17,130 And you can see the different layers are grouped together, 91 00:06:17,130 --> 00:06:22,260 but then the different layers communicate with one another. 92 00:06:22,260 --> 00:06:25,370 And this communication, and this organization is key. 93 00:06:25,370 --> 00:06:28,410 You can have all the different cell types in the retina, 94 00:06:28,410 --> 00:06:31,460 but if they're not arranged in this rigid structure, 95 00:06:31,460 --> 00:06:36,710 or in this specific structure, the retina doesn't function. 96 00:06:36,710 --> 00:06:37,910 3D structures. 97 00:06:37,910 --> 00:06:41,300 We'll talk next time about engineering structure 98 00:06:41,300 --> 00:06:42,320 out of cells. 99 00:06:42,320 --> 00:06:43,940 And the heart is one thing you have 100 00:06:43,940 --> 00:06:45,680 to think about engineering. 101 00:06:45,680 --> 00:06:49,070 The only raw material that you have to use for the engineering 102 00:06:49,070 --> 00:06:51,890 is cells, and so how do you get something 103 00:06:51,890 --> 00:06:54,950 that looks like a human heart, and carries out 104 00:06:54,950 --> 00:07:00,390 the exquisitely regulated pumping function of the heart. 105 00:07:00,390 --> 00:07:02,790 And here's another one that I'll touch on, 106 00:07:02,790 --> 00:07:05,500 which is the question of position. 107 00:07:05,500 --> 00:07:07,210 It's not that we just are made up 108 00:07:07,210 --> 00:07:10,840 of lots of different kinds of cells that are grouped together 109 00:07:10,840 --> 00:07:12,060 in organs. 110 00:07:12,060 --> 00:07:13,840 It's that they're also positioned 111 00:07:13,840 --> 00:07:15,560 in the correct place. 112 00:07:15,560 --> 00:07:17,740 And in this plasticized human-- 113 00:07:17,740 --> 00:07:20,530 actually, I think it's a fully plastic human-- 114 00:07:20,530 --> 00:07:24,550 if you open up the cavity and look into the abdomen, 115 00:07:24,550 --> 00:07:27,760 you can see these organs that are arranged packed 116 00:07:27,760 --> 00:07:29,770 so beautifully like this. 117 00:07:29,770 --> 00:07:31,330 It's no accident. 118 00:07:31,330 --> 00:07:34,000 They get there, because they're told to get there. 119 00:07:34,000 --> 00:07:36,250 There is a process that positions 120 00:07:36,250 --> 00:07:38,080 the organs in the precise way. 121 00:07:38,080 --> 00:07:40,180 And if they're positioned incorrectly, 122 00:07:40,180 --> 00:07:44,320 there are medical consequences, which are very severe. 123 00:07:44,320 --> 00:07:48,170 All right, so all of these things we need to think about. 124 00:07:48,170 --> 00:07:49,990 But let's go back to the board, and you 125 00:07:49,990 --> 00:07:53,140 will recognize this diagram, which 126 00:07:53,140 --> 00:07:57,540 is pivotal for what we're going to talk about today. 127 00:07:57,540 --> 00:08:00,930 Here is a mantra that I've mentioned before. 128 00:08:00,930 --> 00:08:04,470 And you need to know and really need to understand this. 129 00:08:04,470 --> 00:08:07,875 All cells contain the same set of genes. 130 00:08:23,500 --> 00:08:26,870 Professor Jacks will give you one exception to this rule, 131 00:08:26,870 --> 00:08:28,210 but it's the exception. 132 00:08:28,210 --> 00:08:33,179 All cells in your body contain the same set of genes, 133 00:08:33,179 --> 00:08:37,010 but not all those genes are used in every cell type. 134 00:08:40,110 --> 00:08:46,660 But each cell type uses-- 135 00:08:46,660 --> 00:08:49,690 and you know the word expresses now-- 136 00:08:49,690 --> 00:08:55,120 each cell type expresses a subset. 137 00:08:55,120 --> 00:08:56,560 And it's a unique subset-- 138 00:08:56,560 --> 00:08:59,260 well, let me put unique in parentheses, 139 00:08:59,260 --> 00:09:00,730 and you'll see what I mean-- 140 00:09:00,730 --> 00:09:03,415 a unique subset of the genome. 141 00:09:08,550 --> 00:09:12,930 And this set of genes and the products of those genes 142 00:09:12,930 --> 00:09:14,880 make the cell type what it is. 143 00:09:19,170 --> 00:09:30,740 The products of those genes, usually proteins and some RNAs, 144 00:09:30,740 --> 00:09:32,760 give the cell type it's function. 145 00:09:41,450 --> 00:09:43,790 So there are two corollaries here. 146 00:09:43,790 --> 00:09:47,630 One, you have to understand how the expression of genes 147 00:09:47,630 --> 00:09:51,200 is controlled, and that is pivotal to this list. 148 00:09:51,200 --> 00:09:56,120 And two, this set of genes that makes each cell 149 00:09:56,120 --> 00:09:59,600 type, the set of active genes that makes each cell type what 150 00:09:59,600 --> 00:10:04,340 it is, forms a kind of a combinatorial code for a cell 151 00:10:04,340 --> 00:10:05,430 type. 152 00:10:05,430 --> 00:10:07,400 So let's just write this down. 153 00:10:07,400 --> 00:10:10,955 So control of gene expression is crucial. 154 00:10:20,360 --> 00:10:26,370 And there is a combinatorial code 155 00:10:26,370 --> 00:10:29,120 of gene expression for each cell type. 156 00:10:32,390 --> 00:10:40,900 A combinatorial code of expressed genes 157 00:10:40,900 --> 00:10:41,890 for each cell type. 158 00:10:52,150 --> 00:10:55,750 You will not find this notion of a combinatorial code 159 00:10:55,750 --> 00:10:56,380 in your book. 160 00:10:56,380 --> 00:10:58,960 But I think if you talk to any life scientist who's 161 00:10:58,960 --> 00:11:01,210 doing research right now, they would 162 00:11:01,210 --> 00:11:03,460 agree that that is the correct way 163 00:11:03,460 --> 00:11:06,080 to be thinking about cell type. 164 00:11:06,080 --> 00:11:08,100 So let's explore this a bit more. 165 00:11:08,100 --> 00:11:10,630 And let's write out three different cell types. 166 00:11:14,010 --> 00:11:17,052 And I'm going to introduce the word here cell fate. 167 00:11:23,380 --> 00:11:28,680 And both cell type and cell fate can be used interchangeably 168 00:11:28,680 --> 00:11:31,360 with the term function. 169 00:11:31,360 --> 00:11:40,660 And let's pick neurons, muscle, and the epidermis, which 170 00:11:40,660 --> 00:11:42,190 is the outer layer of the skin. 171 00:11:50,270 --> 00:11:52,320 And let's consider the genes that 172 00:11:52,320 --> 00:11:54,720 are present in each cell type. 173 00:11:54,720 --> 00:11:57,690 And let's consider the genes that are 174 00:11:57,690 --> 00:11:59,910 expressed in each cell type. 175 00:12:05,010 --> 00:12:07,140 The genes that are present in each cell type 176 00:12:07,140 --> 00:12:10,180 as I've just told are the same. 177 00:12:10,180 --> 00:12:16,530 And so let's make them A, B, C, D, and E. 178 00:12:16,530 --> 00:12:20,850 And each of those genes is present in each of these cell 179 00:12:20,850 --> 00:12:26,740 types, but only some of them are used. 180 00:12:26,740 --> 00:12:33,100 And so let's say in the neurons A, B, and E are 181 00:12:33,100 --> 00:12:44,860 used, in muscle A, C, and D and A, B, and C in epidermis. 182 00:12:44,860 --> 00:12:46,510 So look at what I've written there. 183 00:12:46,510 --> 00:12:49,810 And you can pick out some patterns. 184 00:12:49,810 --> 00:12:52,240 You can pick out a gene that is expressed 185 00:12:52,240 --> 00:12:54,070 in all of the cell types. 186 00:12:54,070 --> 00:12:59,650 So gene A is expressed in all of the cell types. 187 00:12:59,650 --> 00:13:03,610 And gene A exemplifies a gene that we term ubiquitously 188 00:13:03,610 --> 00:13:06,850 expressed, sometimes termed a housekeeping gene. 189 00:13:06,850 --> 00:13:10,360 I really dislike that term, but you will see it. 190 00:13:14,610 --> 00:13:21,560 So ubiquitous expressed, maybe you'll see housekeeping. 191 00:13:21,560 --> 00:13:23,150 You can come to office hours, and I'll 192 00:13:23,150 --> 00:13:25,820 tell you why I hate that term. 193 00:13:25,820 --> 00:13:28,370 And then you can pick out a gene, 194 00:13:28,370 --> 00:13:31,770 which is expressed in some of the cell types, but not others. 195 00:13:31,770 --> 00:13:35,330 So let's look at B. Here's B expressed 196 00:13:35,330 --> 00:13:40,340 in the neurons in the epidermis, but not in the muscle. 197 00:13:40,340 --> 00:13:43,550 And B would be referred to-- and actually C 198 00:13:43,550 --> 00:13:45,440 is the same way, isn't it? 199 00:13:45,440 --> 00:13:50,730 C is in muscle and epidermis. 200 00:13:50,730 --> 00:13:53,070 B and C would be referred to as genes 201 00:13:53,070 --> 00:13:56,170 with restricted expression. 202 00:13:56,170 --> 00:14:00,430 So B and C would have restricted expression. 203 00:14:03,420 --> 00:14:09,480 And then there's two genes there E and D, 204 00:14:09,480 --> 00:14:13,580 which are only expressed in one of their own cell type, 205 00:14:13,580 --> 00:14:17,090 in neurons or in muscle. 206 00:14:17,090 --> 00:14:21,665 So D and E would be cell type specific genes. 207 00:14:25,640 --> 00:14:30,750 And from this simple example, you can see a number of things. 208 00:14:30,750 --> 00:14:34,010 Firstly, you can get a combinatorial code 209 00:14:34,010 --> 00:14:37,790 that is specific for a cell type without any genes that 210 00:14:37,790 --> 00:14:40,010 are specifically expressed in the cell type. 211 00:14:40,010 --> 00:14:42,260 If you look in the epidermis example, 212 00:14:42,260 --> 00:14:43,850 A, B, and C are expressed. 213 00:14:43,850 --> 00:14:46,520 None of them are a cell type specific. 214 00:14:46,520 --> 00:14:49,430 But nonetheless, they give the combinatorial code 215 00:14:49,430 --> 00:14:51,260 that is the epidermis. 216 00:14:51,260 --> 00:14:53,660 And then the other examples, they each got a cell type 217 00:14:53,660 --> 00:14:56,240 specific gene. 218 00:14:56,240 --> 00:14:59,550 What is a combinatorial code really look like? 219 00:14:59,550 --> 00:15:01,370 Well, to be honest we don't actually know. 220 00:15:01,370 --> 00:15:04,460 There is no cell type for which the combinatorial code 221 00:15:04,460 --> 00:15:06,090 is being worked out. 222 00:15:06,090 --> 00:15:10,070 But you know now there were about 20,000 human genes. 223 00:15:10,070 --> 00:15:12,590 And probably about half of them are 224 00:15:12,590 --> 00:15:15,000 expressed in most cell types. 225 00:15:15,000 --> 00:15:17,960 So the combinatorial code for any given cell type 226 00:15:17,960 --> 00:15:21,140 is going to be thousands and thousands of genes, 227 00:15:21,140 --> 00:15:23,600 which are expressed or not expressed 228 00:15:23,600 --> 00:15:26,760 and which are also expressed at different levels. 229 00:15:26,760 --> 00:15:28,380 And we have to take that into account. 230 00:15:28,380 --> 00:15:30,860 So really finding the combinatorial code is 231 00:15:30,860 --> 00:15:32,360 incredibly difficult. And we don't 232 00:15:32,360 --> 00:15:36,710 know any for any cell type, but the notion is exactly the same. 233 00:15:36,710 --> 00:15:40,130 I want to remind you here with this diagram 234 00:15:40,130 --> 00:15:42,170 that the control of gene expression 235 00:15:42,170 --> 00:15:45,110 to give you the final expressed product 236 00:15:45,110 --> 00:15:49,160 can be anywhere all the way from chromatin structure 237 00:15:49,160 --> 00:15:52,640 through transcription all the way through protein processing 238 00:15:52,640 --> 00:15:54,590 modification and localization. 239 00:15:58,090 --> 00:15:59,950 Good. 240 00:15:59,950 --> 00:16:02,230 All right, so now we have a framework 241 00:16:02,230 --> 00:16:05,350 by which we can think of what a cell type is. 242 00:16:05,350 --> 00:16:07,720 And the question, of course, that you're asking 243 00:16:07,720 --> 00:16:11,320 is, so how does that combine tutorial code get expressed 244 00:16:11,320 --> 00:16:13,429 in each of the cell types? 245 00:16:13,429 --> 00:16:14,470 Let's pose that question. 246 00:16:17,560 --> 00:16:23,040 How does a cell type express its code? 247 00:16:36,550 --> 00:16:38,890 And there's a couple of answers. 248 00:16:38,890 --> 00:16:43,240 The global answer that I'm going to give you to this question 249 00:16:43,240 --> 00:16:43,763 is stepwise. 250 00:16:46,700 --> 00:16:49,750 And let's have stepwise answer one. 251 00:16:53,270 --> 00:16:56,590 The idea-- and we can do this-- 252 00:16:56,590 --> 00:16:57,840 I'm going to do this two ways. 253 00:16:57,840 --> 00:17:01,177 I'm actually going to do this-- 254 00:17:01,177 --> 00:17:02,760 no, I'm not going to do this two ways. 255 00:17:02,760 --> 00:17:07,329 Before we get there, this is a great slide, 256 00:17:07,329 --> 00:17:09,619 which will show you two things. 257 00:17:09,619 --> 00:17:12,760 One, it will show you the expression 258 00:17:12,760 --> 00:17:16,819 patterns of two different genes in the whole organism. 259 00:17:16,819 --> 00:17:18,550 So here is a gene called myoD. 260 00:17:18,550 --> 00:17:22,359 I've shown this to you before that is cell type specific. 261 00:17:22,359 --> 00:17:25,180 It's just expressed in these kind of chevron shape 262 00:17:25,180 --> 00:17:27,849 things, which are the developing skeletal muscles, 263 00:17:27,849 --> 00:17:29,830 the voluntary muscles. 264 00:17:29,830 --> 00:17:32,050 And here are a couple of genes that 265 00:17:32,050 --> 00:17:36,370 are expressed in large regions of the developing animal. 266 00:17:36,370 --> 00:17:38,290 And you can see they're expressed, because 267 00:17:38,290 --> 00:17:42,550 of these colors that are there and the colors 268 00:17:42,550 --> 00:17:47,350 are indicative of where the RNA for that gene is. 269 00:17:47,350 --> 00:17:50,650 The technique that allows you to look in a whole animal 270 00:17:50,650 --> 00:17:54,760 and ask where the RNA is for particular genes are found, 271 00:17:54,760 --> 00:17:57,880 is called in situ hybridization, up here 272 00:17:57,880 --> 00:17:59,470 at the top of the screen. 273 00:17:59,470 --> 00:18:02,350 And the idea is that you take animals-- 274 00:18:02,350 --> 00:18:03,580 here, I've said embryos-- 275 00:18:03,580 --> 00:18:08,470 developing animals, and you fix them, which means you kill them 276 00:18:08,470 --> 00:18:09,820 and you permeabilized them. 277 00:18:09,820 --> 00:18:12,185 You make holes in them, and then you 278 00:18:12,185 --> 00:18:16,960 use the principles of base pairing, where you look and see 279 00:18:16,960 --> 00:18:20,550 where the RNA is using a probe, which 280 00:18:20,550 --> 00:18:25,150 is an antisense RNA for a particular gene of interest. 281 00:18:25,150 --> 00:18:28,240 And you label this antisense RNA. 282 00:18:28,240 --> 00:18:30,730 You mix it with the embryo that's got holes in 283 00:18:30,730 --> 00:18:35,350 or the animal that's got holes, where the RNA for gene x is. 284 00:18:35,350 --> 00:18:38,940 It will base pair to your antisense probe. 285 00:18:38,940 --> 00:18:41,170 You then wash out the extra. 286 00:18:41,170 --> 00:18:44,320 And you look and see where the color that comes from the label 287 00:18:44,320 --> 00:18:45,280 is. 288 00:18:45,280 --> 00:18:48,560 And that color tells you where the RNA for a particular gene 289 00:18:48,560 --> 00:18:49,060 is. 290 00:18:49,060 --> 00:18:52,240 So these colors in the developing animal 291 00:18:52,240 --> 00:18:54,340 tell you where particular RNAs are. 292 00:18:54,340 --> 00:18:56,260 It's a very powerful technique. 293 00:18:56,260 --> 00:18:59,770 And it allows us to figure out which genes are cell type 294 00:18:59,770 --> 00:19:02,920 specific and which genes are more generally expressed. 295 00:19:07,660 --> 00:19:09,635 Let's look at your first handout. 296 00:19:09,635 --> 00:19:11,260 And I'm going to write it on the board, 297 00:19:11,260 --> 00:19:13,180 as well, because this is really important. 298 00:19:13,180 --> 00:19:15,790 And you're going to need to know this for this lecture 299 00:19:15,790 --> 00:19:19,600 and when we get to stem cells, as well. 300 00:19:19,600 --> 00:19:21,090 So you can look on the screen. 301 00:19:21,090 --> 00:19:22,380 You can look on your hand-out. 302 00:19:22,380 --> 00:19:24,750 And I would suggest you write it, as well. 303 00:19:24,750 --> 00:19:27,240 The notion when we're thinking about cell type 304 00:19:27,240 --> 00:19:31,530 is that we start off with cells that don't know who they are. 305 00:19:31,530 --> 00:19:33,390 And they're called uncommitted cells. 306 00:19:38,560 --> 00:19:39,750 They're undecided. 307 00:19:45,070 --> 00:19:50,040 And as they go through life, they get some inputs. 308 00:19:50,040 --> 00:19:52,392 We'll be vague about those. 309 00:19:52,392 --> 00:19:53,100 They're up there. 310 00:19:53,100 --> 00:19:55,130 I'm not going to write them here. 311 00:19:55,130 --> 00:20:00,700 And at that point, they become committed cells. 312 00:20:00,700 --> 00:20:03,525 They are sometimes called determined cells. 313 00:20:08,510 --> 00:20:11,380 And at this point, the cells have decided 314 00:20:11,380 --> 00:20:14,120 what they're going to become. 315 00:20:14,120 --> 00:20:20,180 And later on, those committed or determined cells will go on. 316 00:20:20,180 --> 00:20:28,270 And they will become differentiated cells, 317 00:20:28,270 --> 00:20:31,885 where they have their final fates or their final function. 318 00:20:36,710 --> 00:20:43,750 There's a time metric on this progression. 319 00:20:43,750 --> 00:20:49,000 And the notion really is that as cells go through this decision 320 00:20:49,000 --> 00:20:52,750 making process, they change which genes they 321 00:20:52,750 --> 00:20:57,650 are expressing, such that at the culmination-- 322 00:20:57,650 --> 00:20:59,870 but if you think about this or come and talk to me, 323 00:20:59,870 --> 00:21:01,790 you'll find it's more complicated. 324 00:21:01,790 --> 00:21:04,610 At the culmination, they will be expressing 325 00:21:04,610 --> 00:21:07,170 their combinatorial code. 326 00:21:07,170 --> 00:21:15,420 Uncommitted cells, as they transition to committed cells, 327 00:21:15,420 --> 00:21:19,530 activate a set of genes that I'm going to call regulatory genes. 328 00:21:19,530 --> 00:21:21,180 They're the transcription factors, 329 00:21:21,180 --> 00:21:24,735 the translation factors, the protein processing factors. 330 00:21:34,730 --> 00:21:39,410 And these regulatory genes will then go 331 00:21:39,410 --> 00:21:45,710 and activate a set of genes that I'll call effector genes. 332 00:21:48,590 --> 00:21:50,420 And the effector genes are the ones 333 00:21:50,420 --> 00:21:53,270 that are actually carrying out the function of the cell. 334 00:21:53,270 --> 00:21:54,830 They are the globin that's carrying 335 00:21:54,830 --> 00:21:56,720 the oxygen around the body. 336 00:21:56,720 --> 00:21:58,610 They're the neurofilaments that are 337 00:21:58,610 --> 00:22:01,280 making the neurons long and strong and able 338 00:22:01,280 --> 00:22:02,960 to transmit a signal. 339 00:22:02,960 --> 00:22:06,980 They are the cartones, which make hair cells able to secrete 340 00:22:06,980 --> 00:22:10,100 the hair that actually you see. 341 00:22:10,100 --> 00:22:16,200 So the effector genes are the functioning, the functional 342 00:22:16,200 --> 00:22:16,926 mediators. 343 00:22:20,690 --> 00:22:24,830 And it's this mix of regulatory genes, which 344 00:22:24,830 --> 00:22:28,190 I've written as R, an effector genes, which 345 00:22:28,190 --> 00:22:33,770 I've written as E, which form the combinatorial code 346 00:22:33,770 --> 00:22:34,670 for a cell. 347 00:22:41,530 --> 00:22:43,390 So that's one answer. 348 00:22:43,390 --> 00:22:45,850 And you have more up there, which 349 00:22:45,850 --> 00:22:48,187 we'll come to in a moment. 350 00:22:48,187 --> 00:22:49,645 But let me give you another answer. 351 00:22:55,690 --> 00:23:02,680 It's also the same answer stepwise, 352 00:23:02,680 --> 00:23:06,910 but this answer has to do with the history of an organism. 353 00:23:06,910 --> 00:23:09,010 I've avoided talking about embryos, 354 00:23:09,010 --> 00:23:10,840 until now, because I wanted you to think 355 00:23:10,840 --> 00:23:13,630 about the outcome, the cell types. 356 00:23:13,630 --> 00:23:15,460 But actually, all of this starts-- 357 00:23:15,460 --> 00:23:19,210 cell type formation starts right at the beginning 358 00:23:19,210 --> 00:23:25,050 of an organism's life, when two haploid cells, 359 00:23:25,050 --> 00:23:34,900 the egg and the sperm, magically get together and join to form 360 00:23:34,900 --> 00:23:39,495 a diploid cell, the zygote. 361 00:23:42,700 --> 00:23:49,220 This zygote, which is also a single cell 362 00:23:49,220 --> 00:23:52,850 is itself a magical cell, because it contains 363 00:23:52,850 --> 00:23:57,110 all the information necessary to form whatever organism 364 00:23:57,110 --> 00:23:59,590 is going to be the outcome. 365 00:23:59,590 --> 00:24:05,080 The zygote goes on to form an embryo, 366 00:24:05,080 --> 00:24:08,785 also diploid that contains many cells. 367 00:24:12,520 --> 00:24:20,470 And the embryo goes on to form the diploid adult, also 368 00:24:20,470 --> 00:24:21,700 with many cells. 369 00:24:21,700 --> 00:24:24,310 And in humans, there are about 10 370 00:24:24,310 --> 00:24:32,700 to the 14 cells in the human adult. 371 00:24:32,700 --> 00:24:37,830 And during this process of two single cells, 372 00:24:37,830 --> 00:24:39,900 two dying cells, the egg and the sperm 373 00:24:39,900 --> 00:24:42,870 are with a very finite lifetime, when 374 00:24:42,870 --> 00:24:45,022 those cells fused with one another-- 375 00:24:45,022 --> 00:24:46,980 and we're not going to talk about this any more 376 00:24:46,980 --> 00:24:51,980 than that then this discussion because of time constraints. 377 00:24:51,980 --> 00:24:54,260 When they fuse to form the zygote, 378 00:24:54,260 --> 00:24:57,080 there is an extraordinary process where the zygote is now 379 00:24:57,080 --> 00:24:59,990 resurrected in its life, and it has the capacity 380 00:24:59,990 --> 00:25:02,780 to give rise to the whole organism. 381 00:25:02,780 --> 00:25:05,220 What happens during this process? 382 00:25:05,220 --> 00:25:09,540 Well, firstly, I've pointed out, cells divide. 383 00:25:09,540 --> 00:25:12,060 There's a lot of cell division. 384 00:25:12,060 --> 00:25:15,060 And that's really key to getting different cell types. 385 00:25:15,060 --> 00:25:17,910 You have to have something to work with. 386 00:25:17,910 --> 00:25:21,560 And as they divide, they become different. 387 00:25:30,820 --> 00:25:35,950 According to the list on the screen and on the board above, 388 00:25:35,950 --> 00:25:42,410 the egg, the sperm, in fact, are differentiated cells, 389 00:25:42,410 --> 00:25:45,080 but let's start with the zygote, which 390 00:25:45,080 --> 00:25:52,910 is undetermined or uncommitted and undifferentiated. 391 00:26:00,510 --> 00:26:03,190 And I'm using determined and committed deliberately 392 00:26:03,190 --> 00:26:05,890 interchangeably so you get the idea that the terms are 393 00:26:05,890 --> 00:26:07,370 interchangeable. 394 00:26:07,370 --> 00:26:10,780 So the zygote is undetermined and undifferentiated. 395 00:26:10,780 --> 00:26:13,780 And as it goes through its embryonic stage, 396 00:26:13,780 --> 00:26:26,410 determination starts, continues into the adult. 397 00:26:26,410 --> 00:26:30,160 And later during late stages of embryogenesis 398 00:26:30,160 --> 00:26:33,850 and into the adult cells differentiate and become 399 00:26:33,850 --> 00:26:35,510 their final thing. 400 00:26:35,510 --> 00:26:38,170 So determination starts in the embryo 401 00:26:38,170 --> 00:26:44,740 and sometime later the process of differentiation 402 00:26:44,740 --> 00:26:47,810 starts and continues. 403 00:26:47,810 --> 00:26:50,810 And so that's a second way of actually writing out 404 00:26:50,810 --> 00:26:54,800 the stepwise phenomenon of how cells become different 405 00:26:54,800 --> 00:26:57,830 from one another and how different cell types are 406 00:26:57,830 --> 00:26:59,580 formed. 407 00:26:59,580 --> 00:27:01,937 Let's take a look at some slides here. 408 00:27:01,937 --> 00:27:03,770 And let's take a look at a couple of movies. 409 00:27:03,770 --> 00:27:07,460 This is a movie of the first few weeks of human development. 410 00:27:07,460 --> 00:27:09,650 And what you will be able to see from this 411 00:27:09,650 --> 00:27:13,430 is the enormous increase in size of a human embryo that's 412 00:27:13,430 --> 00:27:17,420 coupled with cell division and also with cell determination. 413 00:27:24,440 --> 00:27:25,730 And it's going to play again. 414 00:27:25,730 --> 00:27:29,450 And what you can see, up until about day 56, 415 00:27:29,450 --> 00:27:33,980 we all had very nice tails, and then they disappeared, 416 00:27:33,980 --> 00:27:35,730 unlike other animals. 417 00:27:35,730 --> 00:27:37,940 But all of these are taken at the same scale. 418 00:27:37,940 --> 00:27:40,340 And so you can get a sense of the huge amount of cell 419 00:27:40,340 --> 00:27:45,870 division that's going on during these first few weeks of life. 420 00:27:45,870 --> 00:27:47,010 Here's a second one. 421 00:27:47,010 --> 00:27:49,230 This is a zebrafish embryo. 422 00:27:49,230 --> 00:27:51,780 And I want you to watch this embryo 423 00:27:51,780 --> 00:27:55,620 as it develops very rapidly much more rapidly than a human 424 00:27:55,620 --> 00:27:59,040 during the first 19 hours of development. 425 00:27:59,040 --> 00:28:01,740 The fish embryo is kind of like a chicken embryo. 426 00:28:01,740 --> 00:28:04,050 There's a big cell called a yolk cell. 427 00:28:04,050 --> 00:28:07,800 And on top of this yolk cell sits a little other cell, 428 00:28:07,800 --> 00:28:09,300 which is the embryo itself. 429 00:28:09,300 --> 00:28:11,520 And it's this little top cell. 430 00:28:11,520 --> 00:28:13,380 Here it's already divided to give rise 431 00:28:13,380 --> 00:28:17,280 to two cells from which the embryo is going to arise. 432 00:28:17,280 --> 00:28:19,320 And so as you watch the movie, you'll 433 00:28:19,320 --> 00:28:22,800 see these two cells dividing into four, into eight, and so 434 00:28:22,800 --> 00:28:23,340 on. 435 00:28:23,340 --> 00:28:27,150 And then you'll be able to see the beginnings of the fish 436 00:28:27,150 --> 00:28:27,690 emerge. 437 00:28:27,690 --> 00:28:29,190 And I'll play it a couple of times 438 00:28:29,190 --> 00:28:32,540 and point out some things to you. 439 00:28:32,540 --> 00:28:36,050 Here's the cell division, taking place. 440 00:28:36,050 --> 00:28:38,190 It's not as rapid as this, but it's of course, 441 00:28:38,190 --> 00:28:39,920 a very rapid process. 442 00:28:39,920 --> 00:28:42,500 And now you have a little cap of cells on the yolk, 443 00:28:42,500 --> 00:28:44,150 and watch what happens. 444 00:28:44,150 --> 00:28:47,840 That cap of cells spreads out to cover up the yolk. 445 00:28:47,840 --> 00:28:49,790 And a lot of cells move to that side 446 00:28:49,790 --> 00:28:52,680 of the embryo, the right hand side of the screen. 447 00:28:52,680 --> 00:28:54,780 Here's the eye emerging in the brain. 448 00:28:54,780 --> 00:28:57,260 And here are the muscles of the fish. 449 00:28:57,260 --> 00:28:59,470 And let's watch it again. 450 00:28:59,470 --> 00:29:00,410 Isn't that cool? 451 00:29:03,640 --> 00:29:05,440 So let me stop it. 452 00:29:05,440 --> 00:29:08,860 Here at this stage, you have got several hundred cells 453 00:29:08,860 --> 00:29:12,514 that are sitting on top of this yolk cell. 454 00:29:12,514 --> 00:29:14,680 This pointer seems to have died, but they're sitting 455 00:29:14,680 --> 00:29:16,610 on top of the yolk cell. 456 00:29:16,610 --> 00:29:20,110 And you will be able to see when I start the movie again 457 00:29:20,110 --> 00:29:23,600 how those cells spread out to cover. 458 00:29:23,600 --> 00:29:24,940 And they are actively doing it. 459 00:29:24,940 --> 00:29:25,750 They know to do it. 460 00:29:25,750 --> 00:29:27,490 They actively spread out to cover 461 00:29:27,490 --> 00:29:29,230 the surface of the embryo. 462 00:29:29,230 --> 00:29:31,330 And then actively a group of them 463 00:29:31,330 --> 00:29:35,260 moves to one side of the embryo to form most of the embryo, 464 00:29:35,260 --> 00:29:37,600 including all the nervous system, the muscles, 465 00:29:37,600 --> 00:29:38,985 the intestines, and so on. 466 00:29:38,985 --> 00:29:39,985 So let's start it again. 467 00:29:44,920 --> 00:29:47,225 There you can see these cells spreading out. 468 00:29:47,225 --> 00:29:48,850 They've spread it out to this-- they've 469 00:29:48,850 --> 00:29:50,560 spread out to this point. 470 00:29:50,560 --> 00:29:53,327 Let's let them spread out some more. 471 00:29:53,327 --> 00:29:53,910 Here they are. 472 00:29:53,910 --> 00:29:56,280 They've completely closed up the yolk. 473 00:29:56,280 --> 00:29:58,500 And if we stop now, you'll see on the right hand 474 00:29:58,500 --> 00:29:59,520 side of the screen. 475 00:29:59,520 --> 00:30:01,570 There's a much thicker group of cells. 476 00:30:01,570 --> 00:30:05,070 They're thousands and thousands of cells now that are there. 477 00:30:05,070 --> 00:30:08,640 Now at this point, if you look at gene expression 478 00:30:08,640 --> 00:30:11,760 in the embryo, you can pick out many different regions 479 00:30:11,760 --> 00:30:13,140 of the future brain. 480 00:30:13,140 --> 00:30:15,150 You can pick out the future intestines 481 00:30:15,150 --> 00:30:18,240 and the future muscles, but there is no differentiation 482 00:30:18,240 --> 00:30:18,840 at this point. 483 00:30:18,840 --> 00:30:20,250 The cells do not know. 484 00:30:20,250 --> 00:30:21,930 The cells have not finished becoming 485 00:30:21,930 --> 00:30:23,370 what they are becoming. 486 00:30:23,370 --> 00:30:31,240 And here as we go on a bit more, here is the eye up front. 487 00:30:31,240 --> 00:30:32,920 And these bumps of the brain. 488 00:30:32,920 --> 00:30:34,960 And then these little chevron shape things 489 00:30:34,960 --> 00:30:38,020 there are the future muscles, your fish fillet. 490 00:30:38,020 --> 00:30:40,690 And there is the fish moving on. 491 00:30:40,690 --> 00:30:42,265 It's really a fantastic process. 492 00:30:45,160 --> 00:30:46,750 Very good. 493 00:30:46,750 --> 00:30:49,330 Let's go back to the board and talk 494 00:30:49,330 --> 00:30:52,900 about this more theoretically. 495 00:30:52,900 --> 00:30:55,140 We have sort of answered a question here. 496 00:30:55,140 --> 00:30:57,720 How does a cell type express it's code? 497 00:30:57,720 --> 00:31:00,690 Well, not all at once, over time and over a series 498 00:31:00,690 --> 00:31:03,290 of many steps. 499 00:31:03,290 --> 00:31:05,530 But that's not actually the whole on answer. 500 00:31:08,190 --> 00:31:11,240 And so let's rephrase the question to make 501 00:31:11,240 --> 00:31:12,440 it a little more precise. 502 00:31:12,440 --> 00:31:16,850 And I've rephrased it by asking, what tells a specific cell type 503 00:31:16,850 --> 00:31:18,005 to express its code? 504 00:31:24,720 --> 00:31:29,430 What tells a specific cell type to express its code? 505 00:31:40,590 --> 00:31:42,521 And the answer is-- 506 00:31:42,521 --> 00:31:44,520 it's just not going to be really helpful to you, 507 00:31:44,520 --> 00:31:45,520 but it will in a moment. 508 00:31:45,520 --> 00:31:48,180 The answer is that there are a bunch of inputs. 509 00:31:48,180 --> 00:31:50,610 There are a bunch of instructions 510 00:31:50,610 --> 00:31:51,670 that the cell gets. 511 00:31:58,060 --> 00:32:00,510 And let's write this out in a kind of theoretical way. 512 00:32:00,510 --> 00:32:02,970 We'll get to the molecules in a moment. 513 00:32:02,970 --> 00:32:04,860 Here again are our uncommitted cells. 514 00:32:09,900 --> 00:32:13,350 And they can be exposed to a number of different molecules. 515 00:32:13,350 --> 00:32:15,990 The inputs-- let me just come clean here. 516 00:32:15,990 --> 00:32:18,480 The inputs are specific molecules. 517 00:32:18,480 --> 00:32:20,730 And as you'll see in a moment, they all 518 00:32:20,730 --> 00:32:24,660 have got something to do with cell signaling or regulating 519 00:32:24,660 --> 00:32:27,390 gene expression. 520 00:32:27,390 --> 00:32:29,510 These uncommitted cells can be exposed 521 00:32:29,510 --> 00:32:30,850 to many different inputs. 522 00:32:30,850 --> 00:32:35,060 Let's take three different inputs. 523 00:32:35,060 --> 00:32:40,760 We'll call them input 1, 2, and 3. 524 00:32:40,760 --> 00:32:45,770 And these inputs through many steps and changes 525 00:32:45,770 --> 00:32:48,790 in gene expression. 526 00:32:48,790 --> 00:32:51,660 And the inputs can be composite. 527 00:32:51,660 --> 00:32:54,570 They don't have to be a single thing. 528 00:32:54,570 --> 00:33:02,610 We'll take those cells into differentiated cell type 1, 529 00:33:02,610 --> 00:33:07,520 cell type 2, or cell type 3. 530 00:33:12,500 --> 00:33:14,930 And cell type 1-- 531 00:33:14,930 --> 00:33:17,700 you know, to belabor this, we'll express 532 00:33:17,700 --> 00:33:24,440 code 1, cell type 2 code 2 et cetera. 533 00:33:24,440 --> 00:33:27,560 As these decisions are made similar to the kinds 534 00:33:27,560 --> 00:33:31,190 of decisions we've looked at in biochemistry previously. 535 00:33:31,190 --> 00:33:33,200 There can be interactions. 536 00:33:33,200 --> 00:33:38,420 And so it may be that as cell type 1 develops, it's actually 537 00:33:38,420 --> 00:33:45,734 inhibits the formation of cell type 2. 538 00:33:45,734 --> 00:33:49,040 And cell type 2, in turn, might be 539 00:33:49,040 --> 00:33:53,640 an inhibitor of the formation of cell type 3. 540 00:33:53,640 --> 00:33:56,660 So there are interactions between cells. 541 00:33:56,660 --> 00:34:00,500 So the inputs can be composite. 542 00:34:00,500 --> 00:34:12,650 They can composed of several molecules factors if you like. 543 00:34:16,489 --> 00:34:22,310 And there's crosstalk, just like the crosstalk 544 00:34:22,310 --> 00:34:24,830 between the receptors that we talked about 545 00:34:24,830 --> 00:34:26,690 in cell-cell signaling. 546 00:34:26,690 --> 00:34:31,429 And that's not surprising, because in fact the inputs 547 00:34:31,429 --> 00:34:33,650 includes cell-cell signaling molecules. 548 00:34:33,650 --> 00:34:38,730 So there's ligands and receptors that we spoke about previously. 549 00:34:38,730 --> 00:34:39,769 So what are the inputs? 550 00:34:49,139 --> 00:34:51,060 And there are two. 551 00:34:51,060 --> 00:34:57,000 One are signals that act between cells, just 552 00:34:57,000 --> 00:34:58,950 like we've been talking about in cell 553 00:34:58,950 --> 00:35:00,870 biology, cell-cell signaling. 554 00:35:04,550 --> 00:35:08,080 And wherever you talk about cell-cell signaling, 555 00:35:08,080 --> 00:35:10,870 it is implicit that you're talking about interactions 556 00:35:10,870 --> 00:35:13,290 between cells. 557 00:35:13,290 --> 00:35:24,450 Ligands, which in development are sometimes called inducers, 558 00:35:24,450 --> 00:35:25,700 acts on the receptor. 559 00:35:31,100 --> 00:35:36,260 And the outcome is to change cell fate. 560 00:35:40,330 --> 00:35:42,880 This is a subset of the signaling interactions 561 00:35:42,880 --> 00:35:45,430 we talked about previously, where the response 562 00:35:45,430 --> 00:35:48,760 here or the response previously was manyfold, 563 00:35:48,760 --> 00:35:51,940 the response here would be to change cell fate. 564 00:35:51,940 --> 00:35:54,790 But there's a second kind of input. 565 00:35:54,790 --> 00:36:05,710 And those are the molecules that are cell autonomous, 566 00:36:05,710 --> 00:36:11,620 also referred to as being inherited factors 567 00:36:11,620 --> 00:36:15,970 and referred to in development as determinants. 568 00:36:15,970 --> 00:36:26,030 And these determinants-- this is what cell autonomous means-- 569 00:36:26,030 --> 00:36:27,485 act within cells. 570 00:36:34,670 --> 00:36:37,880 And so they're not going to be ligands some receptors. 571 00:36:37,880 --> 00:36:40,470 They will be things, for example, 572 00:36:40,470 --> 00:36:41,930 like transcription factors. 573 00:36:49,710 --> 00:36:57,320 Furthermore, both determinants and inducers 574 00:36:57,320 --> 00:37:00,470 can act in a concentration dependent way 575 00:37:00,470 --> 00:37:04,610 so that a small amount would give you one cell fate 576 00:37:04,610 --> 00:37:08,120 and a larger amount would give you a different cell fate. 577 00:37:13,590 --> 00:37:16,110 So it can be concentration dependent. 578 00:37:21,730 --> 00:37:25,110 And in the cases where a signal or a determinant 579 00:37:25,110 --> 00:37:29,110 is concentration dependent, it gets a special name. 580 00:37:29,110 --> 00:37:34,030 It's referred to as a morphogen, for historical, not 581 00:37:34,030 --> 00:37:35,960 particularly logical reasons. 582 00:37:35,960 --> 00:37:38,790 But if you see the term you'll know. 583 00:37:38,790 --> 00:37:42,120 And finally, before we go to some slides, 584 00:37:42,120 --> 00:37:45,720 one can find groups of these inputs, groups 585 00:37:45,720 --> 00:37:48,750 of these regulatory molecules. 586 00:37:48,750 --> 00:37:57,030 So all of these inputs, all of these other regulatory 587 00:37:57,030 --> 00:38:00,630 molecules or regulatory factors. 588 00:38:04,370 --> 00:38:07,040 And they can act spatially in groups. 589 00:38:07,040 --> 00:38:10,460 So you can find regions of the developing embryo, where 590 00:38:10,460 --> 00:38:13,800 there are groups of these molecules acting together. 591 00:38:13,800 --> 00:38:16,520 And where you find these groups, that particular region 592 00:38:16,520 --> 00:38:20,630 of the embryo may have a powerful effect in influencing 593 00:38:20,630 --> 00:38:22,940 the cells which form around it. 594 00:38:22,940 --> 00:38:26,720 And that region, that group of factors in one region 595 00:38:26,720 --> 00:38:28,520 that can influence its surroundings 596 00:38:28,520 --> 00:38:31,150 is called an organizer. 597 00:38:31,150 --> 00:38:40,660 So groups of signals, which are localized, 598 00:38:40,660 --> 00:38:54,590 that is in one place, in one group of cells 599 00:38:54,590 --> 00:39:05,790 can influence the surrounding cells 600 00:39:05,790 --> 00:39:07,600 and is termed an organizer. 601 00:39:10,780 --> 00:39:15,550 And there are many organizers in the body both in the embryo 602 00:39:15,550 --> 00:39:17,170 and in ourselves as we'll discuss 603 00:39:17,170 --> 00:39:19,890 when we talk about stem cells. 604 00:39:19,890 --> 00:39:22,510 Examples of organizers, I'll show you in a moment. 605 00:39:22,510 --> 00:39:24,630 There's something called the Spemann organizer, 606 00:39:24,630 --> 00:39:25,740 which is very famous. 607 00:39:25,740 --> 00:39:29,070 And some of you may have learned about that previously. 608 00:39:29,070 --> 00:39:32,910 And then there are regions, for example, 609 00:39:32,910 --> 00:39:37,350 in the forebrain, the developing cerebrum, 610 00:39:37,350 --> 00:39:39,810 where there is an organizer that actually tells 611 00:39:39,810 --> 00:39:42,960 the different parts of you developing higher cortical 612 00:39:42,960 --> 00:39:44,940 function to form. 613 00:39:44,940 --> 00:39:48,690 So let's look at some slides and some of your handouts. 614 00:39:51,590 --> 00:39:53,210 And I drew these for you, because I 615 00:39:53,210 --> 00:39:56,030 thought it was really important that you got them. 616 00:39:56,030 --> 00:40:00,500 Here is localized determinants, localized regulators 617 00:40:00,500 --> 00:40:01,440 called determinants. 618 00:40:01,440 --> 00:40:03,690 And you see the idea here. 619 00:40:03,690 --> 00:40:04,530 This is important. 620 00:40:04,530 --> 00:40:06,360 This isn't on the board. 621 00:40:06,360 --> 00:40:11,150 Here's the mother cell with these boxes, 622 00:40:11,150 --> 00:40:15,000 where these boxes represent some kind of regulatory factor. 623 00:40:15,000 --> 00:40:18,290 And you can see I've drawn them on one side of the cell, 624 00:40:18,290 --> 00:40:21,740 such that when that cell divides one of the daughters 625 00:40:21,740 --> 00:40:24,860 doesn't get them and one of them does. 626 00:40:24,860 --> 00:40:28,730 And if the boxes are regulatory factors, 627 00:40:28,730 --> 00:40:32,180 the daughter's cell that gets them will go on to do something 628 00:40:32,180 --> 00:40:34,170 different than the one that doesn't. 629 00:40:34,170 --> 00:40:37,860 And you can get two different cell types coming out of this. 630 00:40:37,860 --> 00:40:41,460 And I've listed examples of the many different kinds 631 00:40:41,460 --> 00:40:46,060 of factors that can be determinants. 632 00:40:46,060 --> 00:40:48,780 Here's a real example. 633 00:40:48,780 --> 00:40:51,840 This is an early worm embryo. 634 00:40:51,840 --> 00:40:53,880 Remember, I told you about Professor Horvitz, 635 00:40:53,880 --> 00:40:57,060 who got the Nobel Prize for discovering cell death 636 00:40:57,060 --> 00:40:58,410 processes. 637 00:40:58,410 --> 00:41:01,320 This is the same animal he works on. 638 00:41:01,320 --> 00:41:06,950 And on the top panels are nuclei stained in blue 639 00:41:06,950 --> 00:41:08,870 with this dye called dappy. 640 00:41:08,870 --> 00:41:09,980 Here's the zygote. 641 00:41:09,980 --> 00:41:12,630 Here's the two cell embryo and the 32 cell embryo. 642 00:41:12,630 --> 00:41:16,610 And you can see that there's a nucleus in every cell. 643 00:41:16,610 --> 00:41:18,950 On the bottom are some determinants 644 00:41:18,950 --> 00:41:20,950 that are called pea granules. 645 00:41:20,950 --> 00:41:24,350 Pea granules are composites of protein and RNA. 646 00:41:24,350 --> 00:41:27,860 And they are regulators of where the future germ cells will 647 00:41:27,860 --> 00:41:30,140 form, the future egg and sperm. 648 00:41:30,140 --> 00:41:32,690 Look how these germ-- look how these pea granules 649 00:41:32,690 --> 00:41:34,820 segregate during development. 650 00:41:34,820 --> 00:41:39,140 Here they are on one side of the embryo, even in the zygote, 651 00:41:39,140 --> 00:41:40,820 and then the zygote splits. 652 00:41:40,820 --> 00:41:42,850 Look, one of the two cells gets them more 653 00:41:42,850 --> 00:41:44,300 and the other does nothing. 654 00:41:44,300 --> 00:41:48,560 And at the 32 cell stage, there is one cell out of 32 that 655 00:41:48,560 --> 00:41:50,420 has all of the pea granules. 656 00:41:50,420 --> 00:41:52,580 And they've been excluded or degraded 657 00:41:52,580 --> 00:41:55,310 from the rest of the embryo. 658 00:41:55,310 --> 00:41:57,260 And that is a really beautiful example, 659 00:41:57,260 --> 00:41:59,360 perhaps the most beautiful example 660 00:41:59,360 --> 00:42:02,600 of determinants segregating. 661 00:42:02,600 --> 00:42:05,710 Here's another one, the signaling factor 662 00:42:05,710 --> 00:42:08,360 secreted by neighboring cells. 663 00:42:08,360 --> 00:42:12,110 Uncommitted to cells over time will do something. 664 00:42:12,110 --> 00:42:15,650 There's enough transcription factors and regulatory factors 665 00:42:15,650 --> 00:42:17,570 in all cells that over time they'll 666 00:42:17,570 --> 00:42:20,180 go on to differentiate into something if they're 667 00:42:20,180 --> 00:42:21,830 normal cells. 668 00:42:21,830 --> 00:42:25,760 But there's a signaling cell telling an uncommitted cell 669 00:42:25,760 --> 00:42:31,790 to activate a signaling pathway and go on and make cell type 2. 670 00:42:31,790 --> 00:42:33,650 And these are the inducers, which 671 00:42:33,650 --> 00:42:38,750 are ligands binding to receptors and changing sulfate. 672 00:42:38,750 --> 00:42:42,260 These signaling pathways can act in a concentration dependent 673 00:42:42,260 --> 00:42:46,630 way, as seen on that screen. 674 00:42:46,630 --> 00:42:49,610 And here is the notion of a morphogen, where 675 00:42:49,610 --> 00:42:52,230 a high ligand concentration will give 676 00:42:52,230 --> 00:42:56,250 an output of cell type 2 and low ligand concentration 677 00:42:56,250 --> 00:42:57,810 and output of cell type 3. 678 00:42:57,810 --> 00:43:01,320 And we touched on how this works molecularly, previously, it's 679 00:43:01,320 --> 00:43:03,420 not well understood and is complicated. 680 00:43:06,070 --> 00:43:10,440 This is the most famous example of cells 681 00:43:10,440 --> 00:43:14,040 that can go on and tell other cells what to become. 682 00:43:14,040 --> 00:43:17,520 It's a group of cells that was termed the organizer before it 683 00:43:17,520 --> 00:43:20,640 was clear that there were actually lots of organizers. 684 00:43:20,640 --> 00:43:24,130 And they organized was defined by a graduate student Hilde 685 00:43:24,130 --> 00:43:28,620 Mangold, together with her advisor, Hans Spemann. 686 00:43:28,620 --> 00:43:32,250 Mangold, unfortunately, went on and was killed in an explosion. 687 00:43:32,250 --> 00:43:34,440 Spemann went on to get the first Nobel 688 00:43:34,440 --> 00:43:37,800 Prize for developmental biology in 1935. 689 00:43:37,800 --> 00:43:39,180 It's never seemed fair. 690 00:43:39,180 --> 00:43:41,010 It isn't fair, anyway. 691 00:43:41,010 --> 00:43:43,500 That is a sad story. 692 00:43:43,500 --> 00:43:47,430 Spemann was the preeminent developmental biologist 693 00:43:47,430 --> 00:43:48,690 in the 1920s. 694 00:43:48,690 --> 00:43:52,530 And this is the finding that Dr. Mangold made. 695 00:43:52,530 --> 00:43:58,440 She took an embryo and she removed from the embryo-- 696 00:43:58,440 --> 00:44:00,260 so you not only do you see my calendar-- 697 00:44:00,260 --> 00:44:03,980 you get an insight into the rest of my life. 698 00:44:03,980 --> 00:44:08,210 My husband is a professor over at that other university. 699 00:44:08,210 --> 00:44:13,760 So we have competing teaching schedules today. 700 00:44:13,760 --> 00:44:18,920 So Dr. Mangold took a group of cells from the future back 701 00:44:18,920 --> 00:44:21,380 of the embryo-- we'll talk about this next time-- 702 00:44:21,380 --> 00:44:24,470 and she transplanted them into another embryo. 703 00:44:24,470 --> 00:44:26,420 She transplanted them into the belly. 704 00:44:26,420 --> 00:44:28,700 So she took back cells and put them 705 00:44:28,700 --> 00:44:31,380 in the future belly of a host embryo. 706 00:44:31,380 --> 00:44:33,080 So there's a donor and a host. 707 00:44:33,080 --> 00:44:35,540 And she could see the difference between these embryos, 708 00:44:35,540 --> 00:44:37,430 because they had different pigmentation. 709 00:44:37,430 --> 00:44:38,555 They were different colors. 710 00:44:41,040 --> 00:44:43,310 And then she let them go on and develop. 711 00:44:43,310 --> 00:44:45,560 And this was a hugely difficult experiment 712 00:44:45,560 --> 00:44:48,060 in those days for technical reasons. 713 00:44:48,060 --> 00:44:50,660 But over a period of a couple of months, 714 00:44:50,660 --> 00:44:52,280 these embryos developed. 715 00:44:52,280 --> 00:44:55,350 And what she found was this peculiar embryo, 716 00:44:55,350 --> 00:44:57,740 which is a conjoined twin. 717 00:44:57,740 --> 00:44:59,810 And she could show by looking to see 718 00:44:59,810 --> 00:45:01,910 where the cells she had transplanted in 719 00:45:01,910 --> 00:45:05,570 were, that there was this host embryo that was made of all 720 00:45:05,570 --> 00:45:07,790 the original host tissue. 721 00:45:07,790 --> 00:45:10,220 And there was another embryo joined to it 722 00:45:10,220 --> 00:45:13,970 in this orientation, but that only a little bit 723 00:45:13,970 --> 00:45:19,130 of the second embryo actually came from the donor cells. 724 00:45:19,130 --> 00:45:22,940 Most of the second embryo came from the host cells. 725 00:45:22,940 --> 00:45:26,980 And this was epiphanal, because she could understand 726 00:45:26,980 --> 00:45:29,800 that those donor cells had told the host 727 00:45:29,800 --> 00:45:32,540 tissue to make another embryo. 728 00:45:32,540 --> 00:45:35,530 It was an extraordinary unprecedented finding, 729 00:45:35,530 --> 00:45:39,780 and it gave the notion that cells can tell 730 00:45:39,780 --> 00:45:42,030 other cells what to become. 731 00:45:42,030 --> 00:45:45,180 Does this happen in other animals for sure? 732 00:45:45,180 --> 00:45:48,210 This is from a colleague of mine Jerry Thompson, who 733 00:45:48,210 --> 00:45:51,830 made these conjoined twin frog embryos by organizer 734 00:45:51,830 --> 00:45:53,420 transplants. 735 00:45:53,420 --> 00:45:55,020 Does that happen in humans? 736 00:45:55,020 --> 00:45:55,590 It does. 737 00:45:55,590 --> 00:46:00,240 Conjoined twins come from, we believe, organizers 738 00:46:00,240 --> 00:46:02,460 that have split and have given rise 739 00:46:02,460 --> 00:46:05,220 to two embryos, which don't separate properly 740 00:46:05,220 --> 00:46:05,930 from one another. 741 00:46:08,540 --> 00:46:13,840 And we will stop there and continue on Monday.