WEBVTT 00:13.010 --> 00:16.150 Professor Mark Saltzman: Okay, today we're going to 00:16.146 --> 00:18.916 continue our discussion of cellular principles and lead 00:18.922 --> 00:22.012 into cell culture technology which will be the subject of the 00:22.007 --> 00:26.127 section meeting this afternoon, so just to remind you about the 00:26.132 --> 00:30.522 sections. We've been reading Chapter 5. 00:30.520 --> 00:36.040 We talked last time about some of the basic properties of 00:36.042 --> 00:41.762 cells, their basic architecture and what ways cells are the 00:41.762 --> 00:44.752 same, in what ways cells from 00:44.754 --> 00:50.614 animals, including humans differ from simpler microorganisms like 00:50.611 --> 00:54.531 bacteria. Then we talked a little bit 00:54.527 --> 01:00.367 about the sort of physics of what holds cells together to 01:00.369 --> 01:06.339 form a collection of cells, a tissue and to make up the 01:06.340 --> 01:10.920 structure of our body. Today we want to talk in more 01:10.922 --> 01:15.552 detail about the question of how can cells--if they're the same 01:15.545 --> 01:19.045 and they have the same kind of construction, 01:19.049 --> 01:23.729 and they all contain the same genetic material--how can they 01:23.728 --> 01:28.248 develop into a multi cellular organism that has cells that 01:28.249 --> 01:32.369 differ so greatly in function--that differ as much as 01:32.372 --> 01:36.972 the cells in our brain differ from the cells of our skin or 01:36.972 --> 01:39.632 our liver, or our blood. 01:39.629 --> 01:43.289 What are the sort of basic principles that lead to these 01:43.294 --> 01:47.424 differences between cells? To start out I'm going to 01:47.420 --> 01:51.630 go back to the thinking about development a little bit, 01:51.630 --> 01:55.840 embryonic development, and show you a picture here. 01:55.840 --> 02:00.410 This is a picture of the female reproductive tract. 02:00.409 --> 02:04.629 This is the uterus down here, sort of half of it is shown 02:04.633 --> 02:07.803 with the uterine wall, the fallopian tubes, 02:07.801 --> 02:12.331 and the ovaries. You know that the ovary 02:12.334 --> 02:19.544 produces an egg. An egg is an example of a germ 02:19.544 --> 02:23.064 cell. Has only half of the diploid 02:23.064 --> 02:28.384 chromosomal content that most of the cells, which are called 02:28.384 --> 02:34.054 somatic cells in our body have. Germ line cells sperm and egg 02:34.048 --> 02:39.418 are produced by the process of myosis, and that's reviewed in 02:39.424 --> 02:42.684 the book, where it's a special kind of 02:42.678 --> 02:47.038 cell division that results in the reduction of chromosome 02:47.036 --> 02:51.706 number from two copies of each chromosome down to one copy of 02:51.705 --> 02:55.745 each chromosome. The other germ line cell is the 02:55.747 --> 02:59.647 sperm cell. Fertilization of these two 02:59.652 --> 03:05.602 - where these two cells join occurs in the distal part of the 03:05.596 --> 03:09.446 fallopian tube. The result of fertilization now 03:09.448 --> 03:13.318 is a new cell that is the union of the sperm and the egg, 03:13.319 --> 03:18.309 and it's called the zygote and it contains the diploid number 03:18.314 --> 03:20.504 of chromosomes, genes. 03:20.500 --> 03:24.110 One copy of the chromosome comes from the egg and one copy 03:24.110 --> 03:27.660 of each chromosome comes from the sperm, so this you know 03:27.656 --> 03:29.436 about. This one cell, 03:29.443 --> 03:34.553 this one fertilized cell which is unique because it's the - its 03:34.554 --> 03:39.094 chromosome contains the combination of the sperm and the 03:39.088 --> 03:42.198 egg, develops into an embryo and 03:42.200 --> 03:45.450 then on birth develops into a human. 03:45.449 --> 03:52.559 Each of us has something like 10^(14) cells. 03:52.560 --> 03:57.300 We talked about last time that part of the process of going 03:57.299 --> 04:02.199 from this single cell to multi cellular many celled organisms 04:02.203 --> 04:06.243 like we are is cell division. The cell divides, 04:06.236 --> 04:08.516 and divides, and divides many, 04:08.515 --> 04:12.515 many times and that's one of the signature events of 04:12.523 --> 04:15.513 embryogenesis until we have many, 04:15.509 --> 04:18.489 many cells that make up our bodies. 04:18.490 --> 04:21.510 In that process, cells become different in ways 04:21.512 --> 04:23.752 that appear to be highly organized. 04:23.750 --> 04:28.450 We have tissues like the brain which are assembled to do 04:28.448 --> 04:33.398 functions that are different from any other groups of cells 04:33.403 --> 04:36.833 in the body. They work in concert and they 04:36.828 --> 04:40.518 all have similarities, the same with all of our other 04:40.520 --> 04:42.940 organs. So how does that happen? 04:42.940 --> 04:46.600 Well, it really happens throughout development and it 04:46.604 --> 04:50.714 happens from the first stages. In fact, there are differences 04:50.705 --> 04:54.335 that can be detected upon the first cell division where this 04:54.335 --> 04:57.345 zygote divides through the process of mitosis. 04:57.350 --> 04:59.630 We talked about mitosis last time; 04:59.629 --> 05:02.199 it's described more completely in the chapter, 05:02.199 --> 05:04.369 where two cells are formed from one. 05:04.370 --> 05:07.330 Now, these cells have some differences. 05:07.329 --> 05:11.619 If you could look at these cells you could find differences 05:11.621 --> 05:14.801 between them, there are chemical differences 05:14.802 --> 05:17.912 in the content of each of these cells. 05:17.910 --> 05:21.050 If mitosis occurs the way that it's supposed to, 05:21.048 --> 05:24.518 the DNA that's in each of these cells is the same. 05:24.519 --> 05:29.379 That's one of the properties of mitosis, that the DNA gets 05:29.378 --> 05:34.578 completely duplicated during the S phase, during DNA synthesis 05:34.577 --> 05:37.137 phase. How could these cells be 05:37.144 --> 05:39.964 different then, if they contain the same DNA? 05:39.959 --> 05:43.189 What's a physical mechanism that could lead to differences 05:43.190 --> 05:46.930 between these two cells at this very early stage of development? 05:46.930 --> 05:48.820 Any ideas? 05:51.930 --> 05:56.270 If the DNA is synthesized exactly correctly, 05:56.267 --> 06:00.297 so each one gets the right copies of DNA, 06:00.303 --> 06:04.543 what other differences could there be? 06:04.540 --> 06:05.320 Student: [inaudible]Professor 06:05.322 --> 06:06.362 Mark Saltzman The size of the cells could be different; 06:06.360 --> 06:09.500 maybe mitosis is asymmetrical in some way so that one of the 06:09.504 --> 06:11.854 cells ends up being bigger than the other. 06:11.850 --> 06:16.780 How could size affect the life of the cell? 06:23.060 --> 06:24.330 Student: [inaudible]Professor 06:24.329 --> 06:25.849 Mark Saltzman Different amount of metabolic activity 06:25.846 --> 06:27.636 because one has a greater volume of cytoplasm than the other, 06:27.639 --> 06:30.189 for example, so these are exactly the right 06:30.188 --> 06:33.528 kinds of ideas. There could be differences in 06:33.525 --> 06:38.295 the physics of cell division, this process of separating into 06:38.295 --> 06:42.585 two cells such that even though they both have the same 06:42.588 --> 06:45.438 chromosomes, they both have the same DNA 06:45.443 --> 06:48.513 content, maybe one of the cells entraps something that's 06:48.506 --> 06:52.356 different than the other cells. That difference could have 06:52.360 --> 06:55.760 been generated during the process of fertilization. 06:55.759 --> 07:01.149 The sperm - say this is the one sperm cell that's able to inject 07:01.145 --> 07:05.075 its DNA into the egg, well then this cell has a 07:05.078 --> 07:07.938 polarity. Now, the top is different from 07:07.939 --> 07:11.439 the bottom because the sperm came in this side physically and 07:11.437 --> 07:14.507 not the other side. Remember that these cells are 07:14.507 --> 07:17.767 relatively large compared to bacteria and so diffusion 07:17.773 --> 07:21.043 doesn't occur very quickly over this length scale. 07:21.040 --> 07:25.230 In the time it takes for one cell division to occur, 07:25.231 --> 07:29.671 it could be that this cell entraps a different chemical 07:29.668 --> 07:33.858 composition of the cytoplasm then this entraps, 07:33.860 --> 07:37.980 and that's a well known concept. The only important thing to 07:37.979 --> 07:42.299 realize about that is that these differences start to occur very 07:42.295 --> 07:46.125 early in development. Once you have a difference that 07:46.134 --> 07:50.594 occurs, two cells or difference, those differences can propagate 07:50.592 --> 07:55.302 as the cells continue to divide. What's shown in this 07:55.301 --> 08:00.971 diagram is the progress of the developing embryo as it travels 08:00.972 --> 08:04.322 in time, down the fallopian tube. 08:04.319 --> 08:08.179 There's one division, here it shows it at the 16 cell 08:08.180 --> 08:11.820 stage and then here, and this transformation as it 08:11.818 --> 08:15.158 goes from 16 cells to more like 64 cells. 08:15.160 --> 08:20.270 There's a change in sort of the shape of the overall embryo as 08:20.273 --> 08:23.373 well. It's no longer just a round 08:23.365 --> 08:28.185 spherical mass of cells, but it has some structure. 08:28.189 --> 08:32.239 There's a cluster of cells here, there's a sheet of cells 08:32.241 --> 08:36.291 that forms an outer lining, and what is most noticeable is 08:36.294 --> 08:40.404 this cavity, this fluid filled cavity which begins to develop. 08:40.399 --> 08:44.689 Well, this stage of development is called the 08:44.694 --> 08:49.704 blastocyst and it's at this stage late in this blastocyst 08:49.704 --> 08:55.614 stage that the developing embryo implants in the uterine wall, 08:55.610 --> 09:00.520 and there begins to form an interface with the mother so 09:00.524 --> 09:05.354 that it can be nourished during further development. 09:05.350 --> 09:10.710 The cells of this surrounding sheet have become different in 09:10.707 --> 09:15.787 some way and they develop into the placenta and the extra 09:15.792 --> 09:19.682 embryonic tissues. The cells of this cluster 09:19.675 --> 09:23.895 inside next to the fluid filled cavity is a region of the 09:23.898 --> 09:26.988 blastocyst called the inner cell mass. 09:26.990 --> 09:32.140 It's this group of cells, this subset of cells from the 09:32.137 --> 09:37.477 developing embryo that become the embryo, that become the 09:37.475 --> 09:42.505 organism, become the human. We're going to talk as we 09:42.507 --> 09:46.807 go through about the concept of stem cells and how stem cells 09:46.806 --> 09:50.956 are related to development and what's so special about stem 09:50.961 --> 09:53.041 cells. We're going to talk about 09:53.040 --> 09:57.150 different kinds of stem cells. One of the differences in stem 09:57.151 --> 10:02.011 cell populations that you will hear about is you hear about 10:02.007 --> 10:07.027 embryonic stem cells and you hear about adult stem cells. 10:07.029 --> 10:09.309 Those are obvious what the differences are, 10:09.305 --> 10:11.955 embryonic stem cells are derived from embryos . 10:11.960 --> 10:16.600 It's this - its cells in this region here, this inner cell 10:16.599 --> 10:20.749 mass that that's the source of embryonic stem cells, 10:20.750 --> 10:23.680 cells from inner cell mass here. 10:23.679 --> 10:27.429 Adult stem cells are acquired in some fashion from an adult 10:27.428 --> 10:30.488 organism. During development now this 10:30.494 --> 10:35.174 blastocyst has become implanted. These cells around the outside 10:35.169 --> 10:37.479 form the interface, the placenta, 10:37.484 --> 10:41.464 where the maternal blood circulation meets the embryonic 10:41.461 --> 10:45.731 circulation and nutrients are passed back and forth that way 10:45.729 --> 10:49.489 in a very highly regulated and important way. 10:49.490 --> 10:52.540 This inner cell mass develops into the embryo, 10:52.542 --> 10:56.342 which this here shown at a later stage is beginning to be 10:56.340 --> 11:00.410 clear that it's becoming an organism that looks like us. 11:00.409 --> 11:04.169 There's a region that looks the head, and a region that looks 11:04.172 --> 11:07.582 more like the tail. You can see this region here is 11:07.575 --> 11:10.665 going to develop into one of the upper limbs, 11:10.669 --> 11:14.849 the arms here and the back is different from the front, 11:14.852 --> 11:18.262 the spinal cord is developing in the back, 11:18.259 --> 11:21.759 whereas, the structures that become our intestinal tract is 11:21.758 --> 11:25.928 developing on the other surface. Different kinds of polarity 11:25.928 --> 11:29.068 form, there's a head, and there's a tail, 11:29.065 --> 11:31.495 there's a back, there's a front, 11:31.497 --> 11:35.417 there's a left side and there's a right side. 11:35.419 --> 11:40.199 This is one of the kinds of differences that develop - that 11:40.199 --> 11:45.059 happens during development and cells somehow know where they 11:45.062 --> 11:49.432 are within this developing asymmetrical organism. 11:54.110 --> 11:59.320 How does that happen? It happens through a very 11:59.319 --> 12:06.329 regulated, coordinated slow process of what is called 12:06.328 --> 12:12.098 differentiation. Cells move from a state of 12:12.103 --> 12:19.523 limited differentiation to a state of more differentiation. 12:19.519 --> 12:24.399 The zygote or this fertilized egg is a completely 12:24.399 --> 12:28.739 undifferentiated cell. We'll talk about another word 12:28.736 --> 12:31.736 for this later, but it's a cell that's going to 12:31.743 --> 12:34.493 give rise to all the cells of our body. 12:34.490 --> 12:40.080 As division happens and the developing organism acquires 12:40.075 --> 12:44.515 more and more cells, individual cells become 12:44.522 --> 12:48.852 differentiated, they become more and more like 12:48.852 --> 12:53.662 their final mature form. Cells that are within the 12:53.657 --> 12:58.777 region that becomes the nervous system become less like the 12:58.779 --> 13:02.929 zygote and more like the cells of our brain, 13:02.929 --> 13:06.219 neurons and glia, and cells of the mature brain. 13:06.220 --> 13:11.260 The same way cells that form the limb become more like muscle 13:11.260 --> 13:15.380 cells or skin cells, or the structures that become 13:15.377 --> 13:19.327 the limb. Well, that process occurs in a 13:19.328 --> 13:25.328 series of steps and one of those kinds of steps is shown here. 13:25.330 --> 13:28.750 And this diagram shows what I simply labeled as a stem cell, 13:28.754 --> 13:31.754 so I'm not referring to any particular kind of stem cell 13:31.745 --> 13:34.265 now, but just a cell that has the 13:34.265 --> 13:37.735 stem cell character. What does that mean to have the 13:37.737 --> 13:40.667 stem cell character? It means that if I took this 13:40.670 --> 13:44.010 cell and isolated and watched it, I'd notice that it had a 13:44.010 --> 13:47.610 couple of characteristics. One is that it's capable of 13:47.612 --> 13:50.432 something called asymmetrical division. 13:50.429 --> 13:53.759 We talked about division last time. 13:53.759 --> 13:58.949 We talked about the parent cell forming two identical daughter 13:58.949 --> 14:02.269 cells. An asymmetrical division is not 14:02.273 --> 14:07.223 like that, it's when a parent cell forms two cells that are 14:07.218 --> 14:11.628 different in some way. That difference has functional 14:11.634 --> 14:15.674 consequences for the daughter cells in that one of the 14:15.670 --> 14:19.630 daughter cells becomes what's called here a committed 14:19.630 --> 14:23.200 progenitor cell. It's no longer a stem cell but 14:23.196 --> 14:26.356 it's a progenitor cell. A progenitor cell, 14:26.360 --> 14:30.250 the definition, it just means it can generate 14:30.247 --> 14:35.457 the cells that are typical of that tissue or that organ, 14:35.460 --> 14:41.930 so it's capable of becoming these mature classes of cells. 14:41.929 --> 14:44.749 We'll talk more about this in the context of the brain, 14:44.753 --> 14:47.483 but if we were talking about a stem cell in the brain, 14:47.480 --> 14:51.170 then the result of this asymmetrical division would be a 14:51.173 --> 14:55.273 committed progenitor cell that's capable of forming cells that 14:55.270 --> 14:59.500 are the cell types found in the brain and not cells that are the 14:59.502 --> 15:03.362 cell types found in the liver, or the kidney, 15:03.361 --> 15:06.041 or the spleen, or muscle. 15:06.039 --> 15:10.049 One result of this asymmetrical division is a committed 15:10.052 --> 15:13.452 progenitor cell. The result is a cell that's 15:13.448 --> 15:18.098 very similar but it is - very similar to the progenitor cell - 15:18.098 --> 15:23.188 but it's exactly the stem cell. So this stem cell division 15:23.192 --> 15:28.872 leads to another stem cell as well as a committed progenitor 15:28.870 --> 15:31.380 cell. Now, the differences here may 15:31.378 --> 15:35.028 be subtle in terms of chemical composition or if you put these 15:35.033 --> 15:38.453 cells under a microscope and looked at their analysis. 15:38.450 --> 15:42.850 In terms of function they're very important because this stem 15:42.848 --> 15:47.168 cell which is produced goes back into the population of stem 15:47.173 --> 15:51.643 cells and is able to repeat this process to form new committed 15:51.644 --> 15:55.314 progenitor cells and to form new stem cells. 15:55.309 --> 16:01.089 That's important because one of the attributes of stem cells is 16:01.090 --> 16:06.310 that they remain at their site and capable of reproducing 16:06.311 --> 16:09.141 themselves. This process is called 16:09.141 --> 16:12.011 self-renewal, so that's one important process 16:12.005 --> 16:14.995 of property stem cells, that they're capable of 16:14.998 --> 16:18.368 self-renewal. The other one is a committed 16:18.365 --> 16:23.225 progenitor cell that now somehow has been changed in such a way 16:23.226 --> 16:27.846 that it's going to mature and develop into non-stem cells or 16:27.852 --> 16:30.912 the cells that make up our bodies, 16:30.910 --> 16:33.280 somatic cells. Now, what could these 16:33.275 --> 16:35.665 differences be? They're not chromosomal 16:35.673 --> 16:39.583 differences because this is the ordinary process of mitosis. 16:39.580 --> 16:42.110 So presumably, these two cells have exactly 16:42.106 --> 16:44.986 the same DNA content, but something's been passed 16:44.994 --> 16:48.984 onto this one that wasn't there. This is one of the very 16:48.984 --> 16:53.504 important areas that still is not completely understood in 16:53.504 --> 16:56.774 stem cell biology. What is the difference that's 16:56.774 --> 16:59.324 generated during an asymmetric cell division? 16:59.320 --> 17:02.390 There are types of changes that are known. 17:02.389 --> 17:06.869 Some of them are changes in the - not the sequence of DNA, 17:06.874 --> 17:11.674 not the sequence of nucleotides in the DNA - but the chemistry 17:11.673 --> 17:16.633 of DNA around that the way that it's packed into a nucleus. 17:16.630 --> 17:20.580 So the access that a cell has to certain kinds of genes, 17:20.583 --> 17:23.103 or chemical modifications of DNA, 17:23.099 --> 17:26.739 not chemical modifications that change the base pairs, 17:26.737 --> 17:30.697 that would be a mutation. That can happen but that's 17:30.697 --> 17:35.477 abnormal, but changes in maybe the chemistry of the backbone 17:35.479 --> 17:38.639 that holds the nucleotides together. 17:38.640 --> 17:42.230 In some cases that backbone gets methylated and those 17:42.226 --> 17:45.606 regions of the DNA that are methylated get treated 17:45.605 --> 17:49.325 differently by the cell than unmethylated regions. 17:49.329 --> 17:52.509 You go on and you study developmental biology or 17:52.511 --> 17:55.441 molecular biology, you'll learn more about these 17:55.443 --> 17:57.753 things. For our purpose just - these 17:57.753 --> 18:00.193 are the kinds of changes that can happen. 18:00.190 --> 18:02.840 Or it can the kind of change we talked about before, 18:02.835 --> 18:06.045 where during division there are some chemicals that are trapped 18:06.050 --> 18:07.970 in one cell and not in the other, 18:07.970 --> 18:11.850 and that could lead to a difference we already talked 18:11.852 --> 18:14.292 about. Or it could be not having to do 18:14.288 --> 18:17.788 with the cells themselves but maybe the environment that the 18:17.786 --> 18:21.436 cell finds itself in. We talked last time about 18:21.442 --> 18:26.892 extracellular matrix and this complex protein-carbohydrate gel 18:26.889 --> 18:32.089 that surrounds all cells. Cell division takes place 18:32.094 --> 18:36.374 within an organism. We'll talk in a minute about 18:36.366 --> 18:41.436 stem cells that are involved in generation of blood and they 18:41.438 --> 18:45.218 develop and they live in the bone marrow. 18:45.220 --> 18:48.660 Well, what if this division takes place in an environment 18:48.658 --> 18:52.528 where there's one kind of extra cellular matrix here and another 18:52.526 --> 18:54.856 kind of extracellular matrix here? 18:54.859 --> 18:58.069 Then this cell is going to experience something different 18:58.074 --> 19:00.944 from this cell. It could be those differences 19:00.944 --> 19:04.804 that they experience in their extracellular environment that 19:04.798 --> 19:08.258 lead to their choice to either self-renew or to become 19:08.260 --> 19:09.240 committed. 19:13.519 --> 19:16.199 So that's asymmetrical division and that's a property 19:16.195 --> 19:18.845 of stem cells. The other property is that 19:18.851 --> 19:23.291 these committed progenitor cells that are formed can turn into 19:23.289 --> 19:26.999 something, can turn into more mature cell types. 19:27.000 --> 19:30.840 That process of maturation is called differentiation. 19:34.819 --> 19:36.889 We'll talk more about that and I've already said something 19:36.888 --> 19:37.358 about that. 19:41.069 --> 19:44.789 A capability for asymmetric division and the production of 19:44.792 --> 19:47.672 cells that become differentiating more mature 19:47.665 --> 19:50.665 cells, those are properties of stem cells. 19:50.670 --> 19:54.370 Another concept that's important in thinking about stem 19:54.370 --> 19:58.200 cells is potential. Potential refers to what it 19:58.203 --> 20:03.563 sounds like, 'what potential does this committed progenitor 20:03.559 --> 20:06.439 cell have? ' 'What potential does this 20:06.435 --> 20:09.715 stem cell have?' Well, one way to think about is 20:09.718 --> 20:13.668 that upon this first division, this asymmetric division, 20:13.671 --> 20:17.841 this committed progenitor cell has lost some potential. 20:17.839 --> 20:22.189 It's no longer capable of self-renewal to form another 20:22.194 --> 20:25.054 stem cell. It's gone down a path towards 20:25.051 --> 20:28.151 maturation that's very difficult to go back up. 20:28.150 --> 20:32.990 So there's a loss of potential in this division. 20:32.990 --> 20:37.200 This stem cell which is reproduced still has the 20:37.203 --> 20:43.033 potential to undergo asymmetric division but this one does not. 20:43.029 --> 20:47.529 One sort of, might be kind of simple minded, 20:47.525 --> 20:52.785 but one way to think about potential is with the kind of 20:52.786 --> 20:58.716 potential that we all experience as we develop from newborns to 20:58.716 --> 21:02.816 adults, that a newborn child has lots 21:02.816 --> 21:06.716 of different potential. It doesn't have every 21:06.720 --> 21:11.120 potential, it's a boy or a girl, it's not going to go back, 21:11.119 --> 21:15.249 but it has lots of potential in that eventually when it becomes 21:15.253 --> 21:17.723 an adult it could become a cellist, 21:17.720 --> 21:20.190 or a biologist, or an auto mechanic, 21:20.194 --> 21:24.084 or a biomedical engineer, all those potentials are still 21:24.083 --> 21:26.223 there. As you develop, 21:26.222 --> 21:31.002 as you're educated, you retain all those potentials 21:30.999 --> 21:36.919 for a certain point and then you make choices and you lose some 21:36.921 --> 21:41.321 of those potentials. I'm unlikely to become a 21:41.317 --> 21:45.987 concert cellist at this point. It's not impossible but it's 21:45.994 --> 21:49.754 pretty unlikely. I've probably lost my potential 21:49.745 --> 21:54.105 to be an outstanding cellist. You all could still do that if 21:54.113 --> 21:57.123 you decide too, but it's going to be harder for 21:57.124 --> 22:00.794 you than if you would have started when you were ten, 22:00.789 --> 22:05.409 so you're losing some potential around - along the way. 22:05.410 --> 22:08.660 You're in the process of becoming more mature, 22:08.664 --> 22:12.864 more differentiated and you're losing potential at the same 22:12.859 --> 22:15.189 time. The same thing with these 22:15.185 --> 22:18.415 cells here, as these cells undergo continual divisions, 22:18.420 --> 22:21.310 they're changing in ways that make them mature, 22:21.307 --> 22:24.757 that make them more like the mature cells of the nervous 22:24.759 --> 22:26.089 system, for example, 22:26.092 --> 22:28.822 if that's where they end up being but they're losing 22:28.823 --> 22:32.093 potential as they go through that differentiation process. 22:32.089 --> 22:36.819 Now, one of the great hopes of modern biology is that we can 22:36.815 --> 22:40.815 figure out how to reverse that process in cells. 22:40.819 --> 22:45.859 How we could take cells that are differentiated to some 22:45.863 --> 22:49.603 extent and make them de-differentiate, 22:49.599 --> 22:53.969 to go back in the process of differentiation so that they 22:53.965 --> 22:57.395 gain more potential. Why would that be useful? 22:57.400 --> 23:01.040 Well, it would be useful because if I could take cells 23:01.035 --> 23:04.115 from the skin, find stem cells in the skin and 23:04.121 --> 23:08.101 then de-differentiate them so that they were now capable of 23:08.099 --> 23:10.929 becoming liver, or brain, or things that 23:10.925 --> 23:13.695 they're not going to become in their normal site, 23:13.696 --> 23:16.926 then that could be a very powerful tool for medicine. 23:16.930 --> 23:21.560 So far our ability to de-differentiate cells or find 23:21.556 --> 23:26.276 out how to do that is limited. Does this make sense? 23:26.279 --> 23:29.979 What is actually changing during this process of 23:29.983 --> 23:32.963 differentiation? What's the difference between 23:32.961 --> 23:36.021 this cell which I call a committed progenitor cell and 23:36.017 --> 23:38.267 its offspring, and the offspring of that 23:38.265 --> 23:40.945 offspring. It goes - going through this 23:40.950 --> 23:44.920 process of amplifying divisions, every division increasing the 23:44.917 --> 23:48.687 number of cells by a factor of two and these cells becoming 23:48.688 --> 23:51.288 more differentiated around the way. 23:51.289 --> 23:53.599 I've shown the differences here in terms of shape, 23:53.597 --> 23:56.227 these are shaped liked octagons and these are shaped like 23:56.234 --> 23:58.694 squares, but if I looked at these cells, 23:58.689 --> 24:01.979 what would I find that's really different about them? 24:01.980 --> 24:05.930 What's different from an immature cell and a mature cell? 24:05.930 --> 24:10.420 Well, it's not the DNA; they all have the same DNA. 24:10.420 --> 24:13.130 There might be these, what are called epigenetic 24:13.128 --> 24:16.528 differences that I mentioned changes in the structure around 24:16.528 --> 24:18.798 DNA, and those changes lead to 24:18.802 --> 24:22.722 differences in which fraction of the total genes in the 24:22.718 --> 24:26.778 chromosomes are being expressed by a particular cell. 24:26.779 --> 24:31.769 This is what makes cells different, the number and 24:31.771 --> 24:36.051 quantity of the genes that they express. 24:36.049 --> 24:39.879 Out of all the genes that are on the human genome which 24:39.875 --> 24:42.775 fraction is this particular cell using, 24:42.779 --> 24:46.309 which fraction is it expressing determines what proteins are 24:46.312 --> 24:50.122 present in the cell, determines what work or what 24:50.118 --> 24:53.228 activities the cell can engage in. 24:53.230 --> 25:00.510 What's changing along here is the - what's changing along this 25:00.512 --> 25:06.962 pathway is the expression pattern of genes in cells. 25:06.960 --> 25:10.490 Let me make this a little bit more explicit by talking 25:10.489 --> 25:12.779 about the process of hematopoiesis. 25:12.779 --> 25:18.159 Hematopoiesis is the process of generating new blood cells. 25:18.160 --> 25:26.020 Hemato means blood and poiesis means generation or formation. 25:26.019 --> 25:29.379 You know probably that within your bone marrows there's 25:29.379 --> 25:32.429 populations of cells, there are different kinds of 25:32.427 --> 25:35.967 cells within the bone marrow. Some of them have the 25:35.968 --> 25:40.428 capability of becoming red blood cells which carry oxygen in the 25:40.432 --> 25:42.402 blood. Some of them have the 25:42.404 --> 25:45.904 capability of becoming white blood cells, or leukocytes, 25:45.900 --> 25:48.760 of which there are many different subsets. 25:48.759 --> 25:53.549 Some are called neutrophils and those are responsible for 25:53.545 --> 25:57.615 fighting infection. Some are called lymphocytes, 25:57.618 --> 26:00.058 B-lymphocytes, T-lymphocytes. 26:00.059 --> 26:03.359 We're going to talk about those in more detail in a couple of 26:03.361 --> 26:06.611 weeks when we talk about the immune system because these are 26:06.607 --> 26:09.627 the cells that perform and regulate the functions of our 26:09.633 --> 26:12.333 immune system that protect us from disease. 26:12.329 --> 26:16.989 Some form what are called megakaryocytes which become 26:16.994 --> 26:21.304 platelets, which are responsible for clotting, 26:21.299 --> 26:26.229 for forming a barrier if your circulatory system gets injured 26:26.233 --> 26:30.133 so you don't bleed. All these cells come from 26:30.134 --> 26:34.484 the bone marrow and biologists have traced the formation of 26:34.484 --> 26:38.894 these cells in great detail. In fact, of all the systems of 26:38.893 --> 26:42.573 cellular differentiation that are known in our bodies, 26:42.574 --> 26:45.634 probably hematopoiesis is the best known. 26:45.630 --> 26:49.770 It was the first place where the concept of stem cells was 26:49.770 --> 26:54.270 developed, in that if one looks carefully one can find immature 26:54.273 --> 26:58.723 cells in the bone marrow. If you isolate those immature 26:58.716 --> 27:02.496 cells, some of them are less mature than others, 27:02.502 --> 27:06.372 some of them have more potential than others. 27:06.369 --> 27:09.469 For example, if I isolated this one called 27:09.474 --> 27:12.814 the myeloid cell, it's capable of forming red 27:12.805 --> 27:16.435 blood cells, megakaryocytes and neutrophils. 27:16.440 --> 27:19.680 It's capable of forming all these different cells but it's 27:19.684 --> 27:21.794 not capable of forming lymphocytes. 27:21.789 --> 27:27.279 Another stem cell called the lymphoid stem cell is capable of 27:27.279 --> 27:32.619 forming the B and T lymphocytes. Through many decades of 27:32.622 --> 27:37.672 study, biologists have teased out certain populations of cells 27:37.667 --> 27:42.707 within the bone marrow that are capable of reproducing subsets 27:42.712 --> 27:43.872 of cells. 27:50.019 --> 27:54.539 Now, in the process of doing that they found some very rare 27:54.541 --> 27:58.831 stem cells that are called pluripotent, pluri just means 27:58.828 --> 28:02.568 many potencies. Pluripotent stem cells that are 28:02.566 --> 28:06.416 capable of self-renewal to generate themselves and are 28:06.423 --> 28:10.793 capable of dividing into both bioloid and lymphoid progenitor 28:10.789 --> 28:13.279 cells. This is an example of that 28:13.282 --> 28:17.492 asymmetric division. This pluripotent stem cell is 28:17.487 --> 28:22.767 able to self-renew and it's able - generating committed 28:22.771 --> 28:28.741 progenitors of either the myeloid or the lymphoid lineage. 28:28.740 --> 28:32.330 So if I got these two cells they would be less - they would 28:32.334 --> 28:35.744 have less potential than these. Why is it so hard to find 28:35.738 --> 28:37.718 stem cells? I mentioned that this process 28:37.724 --> 28:40.284 has taken many decades and lots of people studying. 28:40.279 --> 28:46.499 Why has it been so hard and why does it continue to be difficult 28:46.498 --> 28:51.728 to identify these pluripotent cells within tissues? 28:51.730 --> 28:56.160 Well, one reason is that they're present in very small 28:56.155 --> 28:59.325 numbers. Of a million cells in the bone 28:59.330 --> 29:02.530 marrow there might only be one of these. 29:02.529 --> 29:06.609 This might be 1 in 100,000,000,000 or something 29:06.614 --> 29:09.884 like that; don't write down the numbers 29:09.881 --> 29:12.871 I'm just using that for illustration. 29:12.869 --> 29:16.369 These cells are rare and so it's been hard to identify them, 29:16.372 --> 29:19.572 that's part of it. The other part of it is how do 29:19.568 --> 29:22.628 you identify them? How do I know when I've got 29:22.630 --> 29:25.320 this one or this one? In this diagram I'm showing you 29:25.323 --> 29:27.793 it's easy to tell because some are yellow, and some are pink, 29:27.789 --> 29:30.779 and some are blue but that's not the way they come out of the 29:30.781 --> 29:33.271 bone marrow. They're not color-coded, 29:33.268 --> 29:36.438 so how you do you find them? How do you think? 29:36.440 --> 29:40.490 If you were searching for unique populations of cells 29:40.486 --> 29:44.996 within the bone marrow what tools would you use to look for 29:44.999 --> 29:48.639 them? How would you search for these 29:48.635 --> 29:50.705 cells? Well, one way would be to 29:50.713 --> 29:53.893 isolate individual cells and culture them outside the body 29:53.889 --> 29:56.549 and see what they become. That would be a very 29:56.554 --> 29:59.924 straightforward functional way to do it, but you could imagine 29:59.921 --> 30:03.341 that that's very labor intensive because you've got to separate 30:03.344 --> 30:07.264 each individual cell, and you've got to nurture it 30:07.262 --> 30:11.432 and then keep track and study what it becomes. 30:11.430 --> 30:14.380 That turns out to be one really important way that they do it. 30:14.380 --> 30:19.050 The other way that they define - or find stem cells is 30:19.048 --> 30:23.958 that over the years of studying them we've begun to recognize 30:23.962 --> 30:28.762 some of the proteins, the specific proteins that are 30:28.761 --> 30:32.431 produced by these characteristic cells. 30:32.430 --> 30:35.730 This cell here, which is indicated green, 30:35.733 --> 30:39.783 is different than this cell that's colored red. 30:39.779 --> 30:44.169 The difference - the real difference is in what genes its 30:44.166 --> 30:49.016 expressing of the total number of genes in the human genome and 30:49.022 --> 30:53.572 therefore if it's expressing these unique - this unique set 30:53.565 --> 30:56.605 of genes. If I could find the unique set 30:56.609 --> 31:00.099 of proteins that correspond to those genes I could define 31:00.098 --> 31:04.078 chemically what the cell is. It turns out that one of 31:04.084 --> 31:08.194 the places that's been very fruitful to look for proteins 31:08.193 --> 31:12.303 that differ between cell populations is on the surface of 31:12.302 --> 31:14.552 the cell. We talked about the cell 31:14.550 --> 31:17.550 membrane, the plasma membrane separating the inside form the 31:17.550 --> 31:19.700 outside. I mentioned a little bit that 31:19.702 --> 31:22.722 this membrane is not just lipid bilayer but there's also 31:22.723 --> 31:25.363 proteins that are inserted into the membrane. 31:25.359 --> 31:28.849 These proteins have functions that are essential for life of 31:28.850 --> 31:32.100 the cell, they transport molecules back and forth across 31:32.104 --> 31:34.344 the membrane. They also allow their 31:34.335 --> 31:37.885 populations of proteins on the surface of each cell that allow 31:37.894 --> 31:40.174 it to interact with its environment, 31:40.170 --> 31:44.960 they're receptors and cell adhesion receptors like I talked 31:44.962 --> 31:48.102 about last time. The kinds of proteins that sit 31:48.104 --> 31:50.814 on a cell surface and form adhesion junctions with 31:50.806 --> 31:53.336 neighboring cells, that's one class of cells on 31:53.342 --> 31:56.372 the surface. There are - that's one class of 31:56.370 --> 31:58.730 proteins on the surface I'm sorry. 31:58.730 --> 32:02.600 There are proteins that are responsible for receiving 32:02.597 --> 32:06.027 signals, chemical signals. There are proteins, 32:06.027 --> 32:08.857 for example, on the surface of some cells 32:08.864 --> 32:13.124 that bind insulin and respond to the presence of insulin. 32:13.119 --> 32:16.979 We're going to talk more about these kinds of molecules on the 32:16.975 --> 32:19.415 surface next week. For now, just know that 32:19.421 --> 32:21.891 different kinds of cells, one of the ways they're 32:21.888 --> 32:24.768 different is that they express different proteins and the 32:24.766 --> 32:27.746 population of proteins on the surface of different cells is 32:27.746 --> 32:30.576 different. We've learned how to 32:30.576 --> 32:35.216 identify and catalog cells according to the composition of 32:35.223 --> 32:39.953 proteins on the surface and those proteins that distinguish 32:39.951 --> 32:43.621 a cell are often called marker proteins. 32:43.619 --> 32:48.809 They're given names, and we're able to - often the 32:48.812 --> 32:54.012 names are confusing, if you look in the literature 32:54.005 --> 32:58.875 you'll find proteins that are called CD44, 32:58.880 --> 33:02.480 CD3, these are differentiation - cluster differentiation 33:02.479 --> 33:06.539 antigens is what CD stands for but it really means a particular 33:06.537 --> 33:10.657 protein which is present on this cell but not on that cell. 33:10.660 --> 33:17.640 So I can use the presence of those to identify cell 33:17.636 --> 33:20.876 populations. One reason it's been harder 33:20.884 --> 33:22.894 to identify stem cells is that they're so rare; 33:22.890 --> 33:26.080 the other reason is that it's hard to identify the 33:26.079 --> 33:30.049 characteristics of them and it's taken many years to work this 33:30.049 --> 33:34.949 out. In the matopoetic system it's 33:34.949 --> 33:40.249 the most well known. In fact, it's so well known now 33:40.245 --> 33:44.355 that we've identified proteins that stimulate the development 33:44.359 --> 33:49.009 of cells along certain pathways. I talked about one of them a 33:49.005 --> 33:51.885 couple of weeks ago, the protein epo, 33:51.892 --> 33:56.862 erythropoietin called epo is a naturally occurring protein that 33:56.864 --> 34:01.444 is in the bone marrow and it stimulates the development of 34:01.435 --> 34:05.385 red blood cells. So it stimulates these myeloid 34:05.388 --> 34:07.988 cells to develop along this pathway. 34:07.990 --> 34:13.130 It's a protein that's produced by other cells in the body and 34:13.130 --> 34:17.760 when it's enriched in a certain area it stimulates more 34:17.757 --> 34:22.397 production of red blood cells. Because we've learned about 34:22.395 --> 34:26.355 that biology we've been able to make erythropoietin outside the 34:26.356 --> 34:30.016 body and use it as a drug. It can be used - given to 34:30.018 --> 34:34.068 people to - who have certain kinds of anemia to stimulate 34:34.070 --> 34:37.760 blood cell production in a specific kind of way. 34:37.760 --> 34:42.120 There's lots of these so called signaling proteins that have 34:42.123 --> 34:46.143 been identified now. These signaling proteins play 34:46.138 --> 34:50.908 important roles in determining how many cells differentiate 34:50.914 --> 34:55.614 down particular pathways and they turn out also to be very 34:55.607 --> 34:59.887 useful for treating diseases of those pathways. 35:06.000 --> 35:11.130 This pluripotent stem cell from bone marrow is an example 35:11.132 --> 35:14.042 of a stem cell, an adult stem cell, 35:14.040 --> 35:18.830 a stem cell that could be identified from the blood. 35:18.829 --> 35:22.679 Different than the embryonic stem cell we talked about 35:22.677 --> 35:26.377 before, so it's an example of an adult stem cell. 35:26.380 --> 35:30.180 It's also an example of a tissue specific stem cell. 35:30.179 --> 35:35.269 Those stem cells from the blood are capable of becoming all 35:35.270 --> 35:39.580 those cells in the blood. They're not capable of becoming 35:39.577 --> 35:43.957 other kinds of cells in general. Now, you'll hear reports in 35:43.962 --> 35:47.262 the literature, you'll look in the newspaper, 35:47.257 --> 35:51.077 you'll hear about scientists that have found ways to 35:51.077 --> 35:55.097 trans-differentiate cells, that is move them from one 35:55.095 --> 35:58.155 pathway to the other. To find stem cells that they 35:58.157 --> 36:00.827 can move from one kind of pathway to another. 36:00.829 --> 36:04.349 That's been looking at - blood stem cells has been a very 36:04.349 --> 36:08.269 fruitful way to look for that. There are some ways that you 36:08.267 --> 36:11.737 can take stem cells that normally would only produce 36:11.742 --> 36:14.742 blood cells and maintain them in culture, 36:14.739 --> 36:17.339 expose them to certain regimens of chemicals, 36:17.335 --> 36:20.515 do certain manipulations on these cells and they become 36:20.521 --> 36:23.981 capable of producing liver, for example, 36:23.975 --> 36:28.685 or brain, or muscle. That's a lot of the literature 36:28.687 --> 36:32.167 of stem cells that you'll read about, taking a particular 36:32.174 --> 36:35.544 source of stem cell and nurturing it in such a way that 36:35.536 --> 36:39.146 it gains potentials that it didn't have necessarily when it 36:39.147 --> 36:42.967 was in the body, or exploiting those potentials 36:42.966 --> 36:45.986 that it wouldn't necessarily express. 36:45.989 --> 36:53.819 That's a lot of what stem cell biology is like - is about. 36:53.820 --> 36:58.680 This diagram here sort of allows me to walk you through 36:58.681 --> 37:03.791 some of the terminology of this stem cell development and talk 37:03.794 --> 37:07.614 about these concepts. Again, in the context of a 37:07.607 --> 37:10.907 specific tissue site, in this case it's the nervous 37:10.909 --> 37:13.119 system. We started the discussion 37:13.117 --> 37:16.087 talking about the zygote or the fertilized egg. 37:16.090 --> 37:20.950 There's only one source for that, there's only one source of 37:20.948 --> 37:25.128 that fertilized egg. It's not self-renewing, 37:25.133 --> 37:31.223 in that division of the zygote results in two daughter cells 37:31.222 --> 37:36.902 that are no longer the zygote anymore, they're down some 37:36.898 --> 37:40.088 pathway. One way of referring to this 37:40.093 --> 37:43.203 cell is in terms of its potential and the zygote 37:43.204 --> 37:47.314 obviously has the potential of becoming all of the cells of our 37:47.308 --> 37:49.058 body. That's where they all come 37:49.055 --> 37:50.595 from, they all come from the zygote. 37:50.599 --> 37:55.479 The word for that is totipotent, totally potent. 37:55.480 --> 37:58.400 It has the capability of becoming any kind of cell within 37:58.395 --> 38:00.525 the body, in fact, that's what it does. 38:00.530 --> 38:03.570 Further down the line, for example, 38:03.570 --> 38:06.930 in the blastocyst I talked about before, 38:06.929 --> 38:11.149 we could obtain cells from this inner cell mass or this cluster 38:11.148 --> 38:13.528 of cells that becomes the embryo. 38:13.530 --> 38:17.810 Those are called embryonic stem cells, they are self-renewing, 38:17.809 --> 38:21.109 and they are pluripotent, meaning they have many 38:21.107 --> 38:24.367 potencies. That's why people are so 38:24.367 --> 38:29.677 excited about embryonic stem cells because in nature they 38:29.683 --> 38:33.103 become all the cells of the body. 38:33.099 --> 38:38.239 If we understood them well enough we could potentially make 38:38.239 --> 38:43.639 any particular kind of cell in the body from those pluripotent 38:43.643 --> 38:46.173 cells. They're controversial, 38:46.171 --> 38:50.421 I think for obvious reasons, because you have to sacrifice 38:50.423 --> 38:56.803 an embryo in order to get them. Further down this line here 38:56.798 --> 39:03.358 are embryonic - or let's say adult brain stem cells. 39:03.360 --> 39:07.940 These are cells that I - that were obtained either from a more 39:07.943 --> 39:11.403 developed embryo, past the blastocyst stage. 39:11.400 --> 39:13.400 For example, that embryo that I showed on 39:13.396 --> 39:16.286 one of the first slides where there's clearly a head region 39:16.291 --> 39:19.061 and a tail region. Now I isolated these cells 39:19.063 --> 39:22.803 maybe from the head region of the embryo, the region that's 39:22.797 --> 39:26.557 going to develop into the brain, so that would be a good place 39:26.555 --> 39:29.765 to look if you wanted cells that were going to develop into the 39:29.772 --> 39:32.562 brain. They're capable of self-renewal. 39:32.559 --> 39:36.119 They're not quite as potent as the cells from earlier because 39:36.117 --> 39:38.367 they've now differentiated somewhat. 39:38.369 --> 39:41.729 They might be capable of forming all of the cells of the 39:41.731 --> 39:44.231 nervous system; they might still have some 39:44.227 --> 39:47.687 potency to form other things that are similar to the nervous 39:47.692 --> 39:50.112 system. Maybe they could make skin, 39:50.105 --> 39:53.885 maybe they could make other kinds of cells if you treated 39:53.892 --> 39:56.982 them the right way. So they've lost some 39:56.975 --> 40:00.645 capabilities but not many, and these are called 40:00.645 --> 40:04.305 multipotent stem cells. They still have broad potential 40:04.311 --> 40:07.651 and they're self-renewing and so there's much interest in those. 40:07.650 --> 40:11.360 Easiest to find them in embryos but sometimes they can be found 40:11.356 --> 40:15.016 in adult organisms as well. If you go to the right region 40:15.023 --> 40:19.163 of an adult brain you might be able to find cells like this but 40:19.156 --> 40:22.916 it's more difficult. As we've found cells from adult 40:22.916 --> 40:26.936 organisms that seem to be multipotential and studied them 40:26.937 --> 40:31.027 more carefully, some of their potentials turn 40:31.029 --> 40:35.469 out to be lost, they're not exactly the same. 40:35.469 --> 40:38.689 Further down the line here, if we looked in the adult brain 40:38.694 --> 40:41.924 or spinal cord and other regions we'd find committed progenitor 40:41.919 --> 40:44.999 cells. These are cells that are 40:45.003 --> 40:48.853 committed to become nervous tissue. 40:48.849 --> 40:53.409 They might self-renew they might not, they have much more 40:53.412 --> 40:57.552 limited potential than before. You're starting to see the 40:57.552 --> 41:00.912 pattern as I move further and further away from the embryo 41:00.913 --> 41:03.923 from less differentiated to more differentiated, 41:03.920 --> 41:08.240 from non-specific regions to more specific regions, 41:08.236 --> 41:13.236 I'm getting cells that are easier to obtain because you can 41:13.242 --> 41:18.162 obtain them from adult sources but their potential as stem 41:18.163 --> 41:22.373 cells is more limited. There are a couple of 41:22.366 --> 41:26.366 tissues that are of particular interest to scientists and 41:26.367 --> 41:29.937 clinicians now and bone marrow is one of those. 41:29.940 --> 41:32.060 There's a lot of interest in bone marrow and the stem cells 41:32.060 --> 41:34.290 that come from bone marrow and there's a couple of reasons for 41:34.290 --> 41:36.040 this. One is because we understand 41:36.038 --> 41:39.028 the bone marrow system so much better than we understand all 41:39.028 --> 41:42.568 the other stem cell systems. The other is that it's possible 41:42.573 --> 41:45.823 to get stem cells from patients, from bone marrow. 41:45.820 --> 41:48.780 You can collect bone marrow, it's not a procedure that you 41:48.775 --> 41:51.655 would want to do. It involves putting a needle, 41:51.663 --> 41:55.403 a fairly large needle into usually one of the pelvic bones 41:55.404 --> 41:59.014 and collecting marrow from - which is tissue that's deep 41:59.014 --> 42:02.384 inside those bones. It's not as easy as getting 42:02.382 --> 42:05.902 your blood drawn if you give blood to the Red Cross, 42:05.900 --> 42:08.660 for example, but it can be done very safely 42:08.664 --> 42:12.614 and wouldn't it be great if we could identify stem cells that 42:12.613 --> 42:16.563 were multipotent from that bone marrow because you could find 42:16.563 --> 42:20.383 them potentially for - if I needed a treatment that could - 42:20.380 --> 42:24.530 if I had some ailment that could be treated with stem cells then 42:24.527 --> 42:28.407 you could get my own - I could get my own stem cells and use 42:28.411 --> 42:31.731 them. Or maybe I could donate bone 42:31.728 --> 42:36.198 marrow and those stem cells could be given to other people 42:36.202 --> 42:40.682 in the same way that blood can be given to other people by 42:40.677 --> 42:45.227 matching and making sure that immunologically my cells were 42:45.230 --> 42:48.650 compatible with you; there's a lot of interest in 42:48.651 --> 42:50.591 that. There's a lot of interest 42:50.588 --> 42:54.138 in obtaining stem cells from the blood of the umbilical cord on 42:54.135 --> 42:57.125 birth. It turns out that blood within 42:57.126 --> 43:01.826 the umbilical cord is also a rich source of stem cells and 43:01.832 --> 43:05.302 again specific to a particular patient. 43:05.300 --> 43:07.920 There are services now, we don't know yet how to get 43:07.921 --> 43:10.851 those stem cells out of cord blood and how to use them for 43:10.850 --> 43:13.190 therapies, but it's reasonable to think 43:13.190 --> 43:15.680 that we might know about this in 30 years. 43:15.679 --> 43:20.169 So some parents now are choosing to save the cord blood, 43:20.165 --> 43:23.745 have it frozen, locked away somewhere just in 43:23.753 --> 43:27.753 case its useful to their child later in life. 43:27.750 --> 43:30.850 I'm not endorsing that I'm just saying that that's something 43:30.851 --> 43:34.221 that can be done now. I digressed a little from 43:34.222 --> 43:38.622 this diagram but I think you've gotten the picture that as I 43:38.623 --> 43:42.893 move to more adult organisms, as I move to more specific 43:42.890 --> 43:45.280 regions of the brain, for example, 43:45.276 --> 43:49.756 I can still find progenitor cells that have some potential. 43:49.760 --> 43:53.530 It's harder to find, they're more limited numbers, 43:53.526 --> 43:57.056 and in general, more difficult until eventually 43:57.061 --> 44:01.521 down this pathway you have fully differentiated cells, 44:01.519 --> 44:05.729 cells that are fully mature and performing the function of the 44:05.733 --> 44:08.653 mature organ. The two largest populations of 44:08.652 --> 44:12.232 cells within the brain are neurons, the ones that actually 44:12.228 --> 44:15.738 transmit electrical activity and responsible for the main 44:15.741 --> 44:19.131 functions we think of when we think of the brain, 44:19.130 --> 44:22.800 and supporting cells called glia, which are responsible for 44:22.800 --> 44:26.600 sort of creating the right sort of environment for neurons to 44:26.597 --> 44:27.417 function. 44:31.010 --> 44:34.960 I wanted to talk about one last concept and this is one the 44:34.960 --> 44:38.910 boxes from Chapter 5 and you've already been using this in your 44:38.911 --> 44:41.851 homework. I just wanted to talk about one 44:41.853 --> 44:45.743 last concept and that has to do with cell proliferation. 44:45.739 --> 44:50.869 We've been talking about single cell or some subset of cells and 44:50.869 --> 44:56.079 propagating them so that you get a larger population of cells. 44:56.079 --> 44:58.389 Of course this happens all the time in the body. 44:58.389 --> 45:00.829 There are cells within your body that are always in the 45:00.831 --> 45:02.821 process of division and forming new cells, 45:02.820 --> 45:07.350 and sometimes this is for a tissue where cells only have a 45:07.349 --> 45:10.359 finite lifetime. The red blood cells that carry 45:10.357 --> 45:13.357 oxygen only live within your circulation for about a month 45:13.355 --> 45:16.345 and so you have to continually be replacing cells that are 45:16.352 --> 45:19.352 dying and so there are cells that are proliferating. 45:19.349 --> 45:23.319 Cell proliferation is a huge issue in cell culture. 45:23.320 --> 45:29.060 One of the main things that we use cell culture or maintenance 45:29.063 --> 45:35.093 of cells outside the body for is to make more copies of cells. 45:35.090 --> 45:38.080 One of the purposes of cell culture is to make many, 45:38.081 --> 45:41.011 many more cells under controlled conditions where I 45:41.013 --> 45:43.363 can understand what those cells are. 45:43.360 --> 45:46.400 So, in general, when cells are proliferating 45:46.399 --> 45:50.499 they're dividing and they're dividing at a regular rate. 45:50.500 --> 45:54.450 What that means is that one way to describe that mathematically 45:54.450 --> 45:57.350 is shown here. If X is the number of 45:57.351 --> 46:01.251 cells, then the rate of change of X, dX/dt, 46:01.250 --> 46:05.580 the rate of change of the cell population, how fast division is 46:05.584 --> 46:09.434 taking is proportional to the number of cells I have. 46:09.430 --> 46:13.260 This makes sense; the rate at which the cell 46:13.256 --> 46:16.856 population is growing, the derivative dX/dt, 46:16.864 --> 46:20.404 is proportional to the number of cells I have. 46:20.400 --> 46:23.760 The more cells I have the faster they can grow, 46:23.761 --> 46:28.351 fewer cells grows more slowly. This is an example of an 46:28.350 --> 46:33.170 exponential growth process and you're familiar with processes 46:33.174 --> 46:36.154 like these. If you solve this differential 46:36.146 --> 46:39.286 equation, which you don't need to do for the course, 46:39.285 --> 46:42.165 but I show it here; some of you will understand 46:42.170 --> 46:45.570 immediately where this comes from, that means that the number 46:45.570 --> 46:48.570 of cells I have at any particular time is equal to the 46:48.573 --> 46:51.693 number of cells that I have at some starting time, 47:00.942 --> 47:06.102 there's a typo in the book, you can't see it here, 47:15.119 --> 47:18.079 proportionality constant between the number of cells and the rate 47:18.077 --> 47:20.707 of growth is a constant that characterizes how fast a cell 47:20.712 --> 47:23.692 population is growing. Some will be growing very 47:23.689 --> 47:26.589 rapidly, some will be growing less rapidly, 47:26.594 --> 47:30.614 and what this equation shows you here is how to relate that 47:34.761 --> 47:37.871 doubling time of cells. How long does it take for the 47:37.868 --> 47:41.038 population of cells to double? One of the interesting 47:41.036 --> 47:45.376 properties of cells that are in exponential growth is that the 47:45.381 --> 47:49.801 time to increase the cell number by a factor of 2 is always the 47:49.797 --> 47:52.467 same. That makes sense if you think 47:52.470 --> 47:55.240 about this process of cell multiplication, 47:55.242 --> 47:58.962 that I have one cell it becomes 2 cells in a minute, 47:58.960 --> 48:02.940 it could become 4 cells in another minute, 48:02.939 --> 48:08.279 it could become 8 cells in another minute and that's all 48:08.278 --> 48:12.838 that this set of equations is representing. 48:12.840 --> 48:14.010 Questions about that? 48:17.119 --> 48:18.999 Good, I'll see you in section this afternoon. 48:19.000 --> 48:24.000