1 00:00:01 --> 00:00:04 So, when I first came to town, the Red Sox hadn't won for 42 years. 2 00:00:04 --> 00:00:08 Now it's been 86 years, so the whole town all of a sudden changes 3 00:00:08 --> 00:00:13 its psychology. A time for great celebration, 4 00:00:13 --> 00:00:17 at least for you Red Sox fans. At the, after last lecture I had an 5 00:00:17 --> 00:00:21 interesting conversation with one of you. One of you came up to me and 6 00:00:21 --> 00:00:26 said very politely, Professor Weinberg, do you have some 7 00:00:26 --> 00:00:30 lecture notes that you have written out what the important points of the 8 00:00:30 --> 00:00:35 lecture are that you could give me or that you could give us? 9 00:00:35 --> 00:00:39 And I said, you know, I, I'm not really interested in 10 00:00:39 --> 00:00:43 doing that. And the reason I'm not really interested in doing that is 11 00:00:43 --> 00:00:47 that the main function of this course is to enable you to listen to, 12 00:00:47 --> 00:00:51 when somebody is talking about conceptually complex things and to 13 00:00:51 --> 00:00:55 distil what's being said and to figure out in your own mind what's 14 00:00:55 --> 00:00:59 important and what is just another piece of drivel coming out of my 15 00:00:59 --> 00:01:04 mouth or Eric Lander's mouth. In fact, speaking for him, 16 00:01:04 --> 00:01:08 if I will allow, can allow myself, and myself, in the end we don't 17 00:01:08 --> 00:01:12 really care that much whether you know the difference between DNA and 18 00:01:12 --> 00:01:16 RNA or proteins and phospholipids. What we're really interested in 19 00:01:16 --> 00:01:20 doing is to use this course as a vehicle for pushing you to get your 20 00:01:20 --> 00:01:24 brains functioning even better than they already are. 21 00:01:24 --> 00:01:28 And, therefore, if you learn in this course how to, 22 00:01:28 --> 00:01:32 to think about very complex subjects and figure out what's really going 23 00:01:32 --> 00:01:36 on then this course will have more than paid for itself in terms of the 24 00:01:36 --> 00:01:41 energy you put into it. So, that's part of the reason why we 25 00:01:41 --> 00:01:46 don't provide you with lecture outlines. We want you to figure out 26 00:01:46 --> 00:01:51 what's important on your own. Being able to do so will itself be 27 00:01:51 --> 00:01:55 a major triumph. At the end of our discussion last 28 00:01:55 --> 00:02:00 time we talked about the cell cycle, the fact that it has, has four major 29 00:02:00 --> 00:02:05 active phases. G1, S, G2 and mitosis. 30 00:02:05 --> 00:02:09 We talked about mitosis. And we talked about the fact that 31 00:02:09 --> 00:02:14 when cells emerge from mitosis, from M phase in the absence of 32 00:02:14 --> 00:02:18 growth stimulatory factors then they go into G zero. 33 00:02:18 --> 00:02:23 And if they're provided with growth stimulatory factors then they'll go 34 00:02:23 --> 00:02:27 back into the active cell cycle. And this G zero phase we talked 35 00:02:27 --> 00:02:32 about is a quiescence phase, it's a resting phase. 36 00:02:32 --> 00:02:36 In fact, there are two kinds of quiescent cells in our bodies. 37 00:02:36 --> 00:02:40 Those that go into quiescence, non-growth reversibly, and are able 38 00:02:40 --> 00:02:44 to reemerge back into the active cell cycle, and those cells which 39 00:02:44 --> 00:02:48 have irreversibly retreated from the active cell cycle. 40 00:02:48 --> 00:02:52 So, for example, there are many cells in our brain where no matter 41 00:02:52 --> 00:02:56 what you do to them they will never be able to go back into the active 42 00:02:56 --> 00:03:00 cell cycle. And they are, in that sense, considered to be 43 00:03:00 --> 00:03:04 post-mitotic. Post-mitotic meaning that they will 44 00:03:04 --> 00:03:09 never again grow. It's really not clear which of the 45 00:03:09 --> 00:03:13 post-mitotic cells, which tissues in the body harbor, 46 00:03:13 --> 00:03:18 harbor post-mitotic cells. We used to think that most of the 47 00:03:18 --> 00:03:23 differentiated cells in our body are post-mitotic. And when I say 48 00:03:23 --> 00:03:28 differentiated, a topic we will not get into for the 49 00:03:28 --> 00:03:33 moment, what I mean is that different cells in different parts 50 00:03:33 --> 00:03:37 of the body have become differentiated by becoming very 51 00:03:37 --> 00:03:42 specialized to become neurons or becoming liver cells or to becoming 52 00:03:42 --> 00:03:46 skin cells and so forth. And it is probably the case that 53 00:03:46 --> 00:03:50 there are many kinds of differentiated cells in the body 54 00:03:50 --> 00:03:54 which once they differentiate will no longer enter into the active cell 55 00:03:54 --> 00:03:58 cycle. Now, getting back to this. 56 00:03:58 --> 00:04:02 As I also mentioned, if we look at a Petri dish then and 57 00:04:02 --> 00:04:06 we put cells like fibroblast, connective tissue cells in the 58 00:04:06 --> 00:04:10 bottom of the Petri dish, as I told you last time, if you 59 00:04:10 --> 00:04:14 provide those cells with medium which contains all the requisite 60 00:04:14 --> 00:04:18 nutrients, these cells will sit here happily for an extended period of 61 00:04:18 --> 00:04:22 time but will not proliferate. However, if you add to their serum, 62 00:04:22 --> 00:04:26 add their medium, you add serum to this medium. Serum usually comes 63 00:04:26 --> 00:04:30 from cows, so therefore it's called bovine serum. 64 00:04:30 --> 00:04:34 Then the serum, in addition to the nutrients present 65 00:04:34 --> 00:04:39 in the, in the medium will indeed provoke these cells to proliferate, 66 00:04:39 --> 00:04:43 and there are agents in the serum, in fact there are agents which are 67 00:04:43 --> 00:04:48 called growth factors which are contained within the serum which are 68 00:04:48 --> 00:04:53 responsible for inducing these, these cells to begin to proliferate. 69 00:04:53 --> 00:04:57 Well, it's instructive just for a moment to step back and ask 70 00:04:57 --> 00:05:01 ourselves what actually is serum? How do you get serum? 71 00:05:01 --> 00:05:05 And the way you get serum is you take blood and you allow it to clot. 72 00:05:05 --> 00:05:09 And when blood clots the platelets in the, in the blood, 73 00:05:09 --> 00:05:13 platelets are small cellular fragments, they have an intact 74 00:05:13 --> 00:05:16 plasma membrane but they're just, they're very tiny, they don't have a 75 00:05:16 --> 00:05:20 nucleus, and these A, A nuclear fragments, these platelets, 76 00:05:20 --> 00:05:24 when blood is induced to clot the platelets aggregate with one another 77 00:05:24 --> 00:05:28 and you form a big clump, and that, a clot settles to the 78 00:05:28 --> 00:05:32 bottom of the test-tube. But in the context of wounding, 79 00:05:32 --> 00:05:36 let's say you make a cut on your skin, what happens is that blood 80 00:05:36 --> 00:05:40 rushes into the site of, of the, the cut or the wound, 81 00:05:40 --> 00:05:44 clotting occurs in order to create coagulation. And why is there 82 00:05:44 --> 00:05:48 coagulation? In order to staunch the bleeding. In order to prevent 83 00:05:48 --> 00:05:52 there to be further hemorrhage, further loss of blood. But at the 84 00:05:52 --> 00:05:56 same time, as the platelets are aggregating to help form the 85 00:05:56 --> 00:06:00 structure of the clot that, that creates a physical barrier to 86 00:06:00 --> 00:06:04 prevent further bleeding, simultaneously the platelets are 87 00:06:04 --> 00:06:08 releasing a lot of growth factors into the medium around them. 88 00:06:08 --> 00:06:13 Why are they doing that? Because what's happening 89 00:06:13 --> 00:06:18 simultaneous with stopping the bleeding is that the platelets are, 90 00:06:18 --> 00:06:23 are releasing growth factors which are used in order to begin to 91 00:06:23 --> 00:06:28 reconstruct and heal the site of wounding. Consequently, 92 00:06:28 --> 00:06:33 what happens is that the platelets release growth factors. 93 00:06:33 --> 00:06:37 These growth factors stimulate cells right around the sides of the wound 94 00:06:37 --> 00:06:42 which are still viable and have not been destroyed to begin to 95 00:06:42 --> 00:06:46 proliferate in order to reconstruct and intact tissue. 96 00:06:46 --> 00:06:51 One of the most important of these, of these, of these factors that they 97 00:06:51 --> 00:06:55 release is platelet-derived growth factor. Remember GF is 98 00:06:55 --> 00:07:00 just growth factor. And platelet-derived growth factor, 99 00:07:00 --> 00:07:04 or as it's called in the trade PDGF, I mentioned it briefly last time, is 100 00:07:04 --> 00:07:09 a very potent mitogen. A mitogen is a growth stimulatory 101 00:07:09 --> 00:07:14 agent. It's an important mitogen for fibroblasts. 102 00:07:14 --> 00:07:18 Fibroblasts, as you recall, are the connective tissue, the 103 00:07:18 --> 00:07:23 connective tissue cells that are found throughout the body. 104 00:07:23 --> 00:07:28 And, therefore, if you were to, for example, add platelet-derived 105 00:07:28 --> 00:07:32 growth factor, PDGF to those fibroblasts that were 106 00:07:32 --> 00:07:37 sitting there in G zero, PDGF will stimulate the fibroblasts 107 00:07:37 --> 00:07:42 to begin to enter into the active cell cycle, to exit from G zero, 108 00:07:42 --> 00:07:47 to enter into G1, and therefore to complete a, a full cell cycle. 109 00:07:47 --> 00:07:51 And, by the way, recall what I said before, 110 00:07:51 --> 00:07:55 that after the cells leave the active, leave G zero and move 111 00:07:55 --> 00:07:59 throughout the active cell cycle and they have a lot of growth factors, 112 00:07:59 --> 00:08:03 they'll go all the way around the active growth cycle to mitosis. 113 00:08:03 --> 00:08:07 And when they emerge from mitosis, once again they'll ask themselves 114 00:08:07 --> 00:08:12 the question whether it's a good idea to continue to be in the active 115 00:08:12 --> 00:08:16 cell cycle or whether they should exit into G zero, 116 00:08:16 --> 00:08:21 perhaps doing so reversibly. Interestingly, if you look at the 117 00:08:21 --> 00:08:25 way that the cell cycle is organized then what you see is the following, 118 00:08:25 --> 00:08:30 if I can draw the cell cycle again. Here's G1. 119 00:08:30 --> 00:08:34 Here's S phase. And here's G2. And right at, 120 00:08:34 --> 00:08:38 at a distinct point toward the end of G1 is something called the 121 00:08:38 --> 00:08:42 restriction point, which is going to be very 122 00:08:42 --> 00:08:46 interesting shortly. And what happens is after cells 123 00:08:46 --> 00:08:50 emerge from G, from mitosis and they move 124 00:08:50 --> 00:08:54 throughout the, the most of G1 they're continually 125 00:08:54 --> 00:08:58 assessing their extracellular environment to determine whether or 126 00:08:58 --> 00:09:02 not there are enough growth factors around to justify their continuing 127 00:09:02 --> 00:09:07 the rest of the cell cycle. And ultimately they'll reach this 128 00:09:07 --> 00:09:11 restriction point, or as it's sometimes called the R 129 00:09:11 --> 00:09:15 point, and here they will make the final go versus no-go decision. 130 00:09:15 --> 00:09:19 So, if there have historically been enough growth factors from the 131 00:09:19 --> 00:09:23 beginning of G1 all the way to the R point then cells will commit 132 00:09:23 --> 00:09:27 themselves essentially irreversibly to going through the entire rest of 133 00:09:27 --> 00:09:31 the cell cycle, through M. Conversely, if cells reach up to 134 00:09:31 --> 00:09:35 this R point and they calculate that there are enough, 135 00:09:35 --> 00:09:39 there are not enough mitogenic growth factors to justify 136 00:09:39 --> 00:09:43 proliferation then they'll jump out of the active cell cycle and go back 137 00:09:43 --> 00:09:46 to G zero. What that means, in effect, is as follows. Once the 138 00:09:46 --> 00:09:50 cells have passed through the R point and they're over here and they 139 00:09:50 --> 00:09:54 are committed to complete the rest of the cell cycle then you can take 140 00:09:54 --> 00:09:58 growth factors out of their medium and they don't care because they 141 00:09:58 --> 00:10:02 only want to receive these stimulatory signals. 142 00:10:02 --> 00:10:06 They only care about in this window of time. Hereafter, 143 00:10:06 --> 00:10:11 they're committed essentially irreversibly to go through the rest 144 00:10:11 --> 00:10:15 of the cell cycle. There are, as it turns out, 145 00:10:15 --> 00:10:20 also growth inhibitory factors. So, here we've been talking about 146 00:10:20 --> 00:10:25 mitogens, the growth inhibitory factors. So, an important growth 147 00:10:25 --> 00:10:30 inhibitory factor is, for example, TGF beta. 148 00:10:30 --> 00:10:34 And TGF beta works exactly opposite to PDGF because it is a single which 149 00:10:34 --> 00:10:38 is present in extracellular space and tells the cell it should stop 150 00:10:38 --> 00:10:42 proliferating. And, therefore, 151 00:10:42 --> 00:10:47 TGF beta, if it's present in large amounts in this part of the cell 152 00:10:47 --> 00:10:51 cycle, if the cell experiences it in large amounts, 153 00:10:51 --> 00:10:55 that will influence the cell not to move through the restriction point. 154 00:10:55 --> 00:10:59 Conversely, if it's absent then obviously PDGF can have the, 155 00:10:59 --> 00:11:04 the undiluted tensions of the cell. And, therefore, 156 00:11:04 --> 00:11:08 what I'm trying to convey by this is to tell you that cell balances both 157 00:11:08 --> 00:11:12 its growth stimulatory and growth inhibitory signals that it's 158 00:11:12 --> 00:11:16 receiving from extracellular space, these decisions are weighed, and 159 00:11:16 --> 00:11:20 finally down here the cell with make the, the binary decision to go ahead 160 00:11:20 --> 00:11:24 or not to go ahead, depending on historically how many 161 00:11:24 --> 00:11:29 of these factors its recruited in this specific window of time. 162 00:11:29 --> 00:11:33 Recall, as we said last time, that once a growth factor like PDGF 163 00:11:33 --> 00:11:37 goes to the plasma membrane it encounters a receptor on the surface 164 00:11:37 --> 00:11:42 which let's say we call the PDGF receptor. And I'll just draw it 165 00:11:42 --> 00:11:46 like this for the moment. It's a transmembrane protein. 166 00:11:46 --> 00:11:51 The extracellular domain is on the outside. And I'm drawing two copies 167 00:11:51 --> 00:11:55 of the PDGF receptor here for reasons that will become 168 00:11:55 --> 00:12:00 apparent in a moment. And what happens is that PDGF which, 169 00:12:00 --> 00:12:04 for example, can be itself a dimer-, it can be a dimeric growth factor. 170 00:12:04 --> 00:12:09 So, it has two distinct subunits in it. They're both essentially 171 00:12:09 --> 00:12:13 equivalent to one another but it is dimeric. And this dimeric structure, 172 00:12:13 --> 00:12:18 PDGF, allows it to bind to two growth factor receptors 173 00:12:18 --> 00:12:22 simultaneously. Well, why is that interesting? 174 00:12:22 --> 00:12:27 It's interesting for the following reason. 175 00:12:27 --> 00:12:31 These transmembrane PDGF receptors, like the ones I've indicated right 176 00:12:31 --> 00:12:35 here, they're anchored in the plasma membrane because there's a portion 177 00:12:35 --> 00:12:39 of their sequence right in here in the transmembrane domain, 178 00:12:39 --> 00:12:43 I'm indicating it here in the orange, which contains highly hydrophobic 179 00:12:43 --> 00:12:47 amino acids. And those hydrophobic amino acids obviously love to be in 180 00:12:47 --> 00:12:51 this hydrophobic environment of the lipid bilayer and their, 181 00:12:51 --> 00:12:55 by they don't, they have no effect at all on whether the PDGF receptors 182 00:12:55 --> 00:13:00 can move, can traverse in the plane of the plasma membrane. 183 00:13:00 --> 00:13:03 So, the PDGF receptors can move across the face of the plasma 184 00:13:03 --> 00:13:07 membrane. These ones can move to the right or the left, 185 00:13:07 --> 00:13:10 but they're not going to come in or out because they're anchored in this 186 00:13:10 --> 00:13:14 lipid bilayer by this stretch of hydrophobic amino acids. 187 00:13:14 --> 00:13:17 Now, what happens interestingly when PDGF, the dimeric receptor 188 00:13:17 --> 00:13:21 binds to two of these PDGF receptor molecules, which, 189 00:13:21 --> 00:13:24 as I told you, have lateral freedom to translate laterally on the plane 190 00:13:24 --> 00:13:28 of a plasma membrane, what happens is it will bind two of 191 00:13:28 --> 00:13:32 these receptors. And, in so doing, 192 00:13:32 --> 00:13:36 it will pull the two receptor molecules next to one another. 193 00:13:36 --> 00:13:41 Previously, they were just floating around in the plane of the plasma 194 00:13:41 --> 00:13:46 membrane having bound their ligand, recall that PDGF is considered a 195 00:13:46 --> 00:13:50 ligand for the PDGF receptor, having, it will cause these two 196 00:13:50 --> 00:13:55 receptor molecules to now become, become pulled very close to one 197 00:13:55 --> 00:14:00 another. So, I'll redraw it now like this. 198 00:14:00 --> 00:14:03 Now these two receptor molecules look like this, 199 00:14:03 --> 00:14:07 they're right, they're cheek by jowl, they're right next to one another, 200 00:14:07 --> 00:14:11 and this has some interesting consequences. Of great interest 201 00:14:11 --> 00:14:15 here is the affect this has on the ability of the PDGF receptor to emit 202 00:14:15 --> 00:14:18 signals into the cytoplasm. Because recall that the end game 203 00:14:18 --> 00:14:22 here is always how does the, how does the intracellular part of 204 00:14:22 --> 00:14:26 the cell know that this, there's been an encounter with the 205 00:14:26 --> 00:14:30 growth factor in the extracellular space? 206 00:14:30 --> 00:14:35 And this signal-emitting power to PDGF receptor comes from the fact 207 00:14:35 --> 00:14:40 that once these two domains are brought together, 208 00:14:40 --> 00:14:45 each of these two domains is able to modify the other and change the 209 00:14:45 --> 00:14:50 other, i.e., subunit A modifies subunit B, subunit B modifies 210 00:14:50 --> 00:14:55 subunit A. And how is this modification achieved? 211 00:14:55 --> 00:15:00 For the follow, it is achieved in the following way. 212 00:15:00 --> 00:15:04 That the, this domain, which I've been calling, 213 00:15:04 --> 00:15:08 I've just been writing like this, as a rectangle, is actually a 214 00:15:08 --> 00:15:13 catalytic agent. It's actually a tyrosine kinase. 215 00:15:13 --> 00:15:17 So, it's an enzyme. And a tyrosine kinase is an enzyme that takes the 216 00:15:17 --> 00:15:22 gamma phosphate from ATP, the high energy phosphate from APT, 217 00:15:22 --> 00:15:26 ATP and transfers it to tyrosine amino acids that are present 218 00:15:26 --> 00:15:31 on substrates. So, if here is an amino acid 219 00:15:31 --> 00:15:35 sequence in the single letter, letter code, and if we admit that Y 220 00:15:35 --> 00:15:40 is the, is the code for tyrosine then if here's a protein that it 221 00:15:40 --> 00:15:44 functions as a substrate for a tyrosine kinase, 222 00:15:44 --> 00:15:48 a tyrosine kinase will add a phosphate group to the side chain of 223 00:15:48 --> 00:15:53 the tyrosine, which I'm not drawing here, but tyrosine has a hydroxyl 224 00:15:53 --> 00:15:57 group in its side chain and, therefore, it will phosphorilate 225 00:15:57 --> 00:16:02 this tyrosine. That is to say will tetraphosphate 226 00:16:02 --> 00:16:06 group do it? It will phosphorilate this tyrosine. 227 00:16:06 --> 00:16:11 So, these two rectangles are, in fact, tyrosine kinases. And what 228 00:16:11 --> 00:16:16 happens, after the two subunits of the receptor have been brought 229 00:16:16 --> 00:16:20 together, is thereafter, what one finds is that each of these 230 00:16:20 --> 00:16:25 receptor subunits becomes multiply phosphorilated. 231 00:16:25 --> 00:16:30 And each of these lollipops that I'm indicating here are sites where 232 00:16:30 --> 00:16:35 there, a tyrosine residue has become phosphorilated. 233 00:16:35 --> 00:16:38 In fact, there's a tail of the PDGF receptor that extends even further 234 00:16:38 --> 00:16:42 to the cytoplasm which also acquires a number of different phosphates on 235 00:16:42 --> 00:16:46 it. And, again, I'd remind us that this 236 00:16:46 --> 00:16:50 phosphorylation is really what's often called transphosphorylation 237 00:16:50 --> 00:16:53 because each receptor molecule phosphorilates the tyrosine residues 238 00:16:53 --> 00:16:57 on the other. Obviously, when these two receptor molecules 239 00:16:57 --> 00:17:01 are far apart in the plain of the plasma membrane, 240 00:17:01 --> 00:17:05 this transphosphorylation cannot occur. 241 00:17:05 --> 00:17:09 But once the two tyrosine kinase residues, once the two tyrosine 242 00:17:09 --> 00:17:13 kinases have been brought together, pulled together by the dimerization 243 00:17:13 --> 00:17:17 of the receptor, now this cross-phosphorylation, 244 00:17:17 --> 00:17:22 on each phosphorylating the other can occur, and soon the receptors 245 00:17:22 --> 00:17:26 are highly phosphorilated. All of these phosphate groups, 246 00:17:26 --> 00:17:30 to repeat myself, being attached to tyrosine residues in their 247 00:17:30 --> 00:17:35 cytoplasmic domains. And this, in turn, 248 00:17:35 --> 00:17:39 creates interesting docking sites for a variety of other cytoplasmic 249 00:17:39 --> 00:17:44 signaling proteins. And we'll talk about some today and 250 00:17:44 --> 00:17:49 next time, but what I want to leave you with is the following impression. 251 00:17:49 --> 00:17:53 That after this phosphorylation actually occurs there are a number 252 00:17:53 --> 00:17:58 of molecules in the cytoplasm, signaling molecules that have 253 00:17:58 --> 00:18:03 affinity for binding these phosphotyrosines. 254 00:18:03 --> 00:18:07 When I say phosphotyrosine, obviously, I'm referring to the 255 00:18:07 --> 00:18:11 phosphorilated form of tyrosine that's been created by a tyrosine 256 00:18:11 --> 00:18:15 kinase enzyme. So, here's one molecule that can 257 00:18:15 --> 00:18:19 bind. Here's molecule A combined to one of these phosphates, 258 00:18:19 --> 00:18:23 another one combined to this phosphate specifically, 259 00:18:23 --> 00:18:27 and each of these molecules, once they're attracted to this 260 00:18:27 --> 00:18:31 phosphorilated receptor, can then emit downstream signals, 261 00:18:31 --> 00:18:35 send a variety of signals into the cell that ultimately end up in 262 00:18:35 --> 00:18:40 persuading the cell to proliferate. 263 00:18:40 --> 00:18:45 And so these effects here of growth factors in the G1 phase of the cell 264 00:18:45 --> 00:18:50 cycle are mediated by this transmembrane signaling, 265 00:18:50 --> 00:18:55 by the activation of these, of this PDGF receptor, for example, 266 00:18:55 --> 00:19:00 and by the resulting a release of downstream signals into the cell 267 00:19:00 --> 00:19:05 which pursued the cell to proliferate or not to proliferate. 268 00:19:05 --> 00:19:08 To be sure the, when platelets clot, 269 00:19:08 --> 00:19:12 when platelets aggregate and they release PDGF, they also release 270 00:19:12 --> 00:19:15 other kinds of growth factors. For instance, there's another 271 00:19:15 --> 00:19:19 growth factor that's called IGF1, insulin-like growth factor, and that 272 00:19:19 --> 00:19:22 has its own receptor on the surface of cells. And there are, 273 00:19:22 --> 00:19:26 on a cell, hundreds to thousands of these PDGF receptors, 274 00:19:26 --> 00:19:30 there are IGF receptors, there are EGF receptors. 275 00:19:30 --> 00:19:34 And a cell often will require several distinct kinds of growth 276 00:19:34 --> 00:19:38 factor activations in order to proliferate. So, 277 00:19:38 --> 00:19:42 this is only a minor part of the entire exposure that a cell 278 00:19:42 --> 00:19:47 experiences in the G1 phase of the cell cycle. To elaborate on a point 279 00:19:47 --> 00:19:51 that I made last time, an important biological distinction 280 00:19:51 --> 00:19:55 between normal cells and cancer cells is the fact that cancer cells 281 00:19:55 --> 00:19:59 require relatively little growth factors or in the medium in order to 282 00:19:59 --> 00:20:04 proliferate. Normal cells have a very strong 283 00:20:04 --> 00:20:08 requirement for growth factors in their medium. And, 284 00:20:08 --> 00:20:13 therefore, what we can already imagine is the following kind of 285 00:20:13 --> 00:20:17 scenario. That cancer cells have someone deregulated this signaling 286 00:20:17 --> 00:20:21 pathway. Somehow they have become independent of the stimulation that 287 00:20:21 --> 00:20:26 is normally required, usually required for cells to 288 00:20:26 --> 00:20:30 proliferate. And, in fact, we know of several 289 00:20:30 --> 00:20:35 different ways by which cancer cells can acquire this independence. 290 00:20:35 --> 00:20:39 One of the most important ways, it's, it a really interesting one, 291 00:20:39 --> 00:20:43 is here's a cancer cell, which we'll talk about very shortly. 292 00:20:43 --> 00:20:47 And what you find in certain kinds of cancer cells is that the cancer 293 00:20:47 --> 00:20:52 cells themselves release growth factors into the medium. 294 00:20:52 --> 00:20:56 So, there are certain kinds of cancer cells that will release, 295 00:20:56 --> 00:21:00 let's say, a growth factor that's like EGF into the medium around it, 296 00:21:00 --> 00:21:05 around themselves. Well, you'll say that's kind of 297 00:21:05 --> 00:21:09 amusing. But so what. The important part here is that 298 00:21:09 --> 00:21:13 these same cancer cells have receptors for TG, 299 00:21:13 --> 00:21:17 for EGF on their surface. So, they're producing a growth 300 00:21:17 --> 00:21:21 factor and they can also respond to the same growth factor. 301 00:21:21 --> 00:21:25 And, therefore, this EGF, once it's released, can swim over 302 00:21:25 --> 00:21:29 here, activate the receptor and pursued the cell to start 303 00:21:29 --> 00:21:33 proliferating. This is, if you will, 304 00:21:33 --> 00:21:37 a positive feedback loop. But note here importantly that this, 305 00:21:37 --> 00:21:41 the growth of this cell is not being controlled by growth factors coming 306 00:21:41 --> 00:21:45 from cells elsewhere in the tissue or the body. Here we're not talking 307 00:21:45 --> 00:21:49 about different cells talking to one another. Here we're talking about a 308 00:21:49 --> 00:21:53 monologue where this cell is talking to itself. This is sometimes called 309 00:21:53 --> 00:21:57 autocrine signaling and refers to the fact that certain kinds of 310 00:21:57 --> 00:22:02 cancer cells are able to make growth factors to which they can respond. 311 00:22:02 --> 00:22:05 In fact, in normal tissues it's rare for a single cell type in a normal 312 00:22:05 --> 00:22:09 tissue to be able to make a growth factor and to be able to respond to 313 00:22:09 --> 00:22:13 the same growth factor. Why can it normally not respond to 314 00:22:13 --> 00:22:17 that growth factor? Because it won't make the receptor 315 00:22:17 --> 00:22:21 for the growth factor. For example, epithelial cells like 316 00:22:21 --> 00:22:25 the cells in your skin or the cells lining the gut, 317 00:22:25 --> 00:22:29 they can release PDGF, but they don't have a PDGF receptor 318 00:22:29 --> 00:22:32 on their surface. And, therefore, 319 00:22:32 --> 00:22:36 even though they release copious amounts of PDGF, 320 00:22:36 --> 00:22:40 that will not result in this auto stimulatory proliferation and, 321 00:22:40 --> 00:22:44 therefore, you don't have this decontrolled self-proliferation that 322 00:22:44 --> 00:22:48 you see often in cancer cells, this autocrine loop. In many kinds 323 00:22:48 --> 00:22:52 of cancer cells you have another alteration of this growth factor 324 00:22:52 --> 00:22:56 signaling pathway. And here what we see is the 325 00:22:56 --> 00:23:00 following. Instead of there being a small number of growth factor 326 00:23:00 --> 00:23:04 receptors on the cell surface, now there are ten or twenty or fifty 327 00:23:04 --> 00:23:08 times more than are normally present on the cell surface. 328 00:23:08 --> 00:23:11 In other words, this growth, the growth factor 329 00:23:11 --> 00:23:14 receptors are what is called overexpressed. 330 00:23:14 --> 00:23:23 And, therefore, 331 00:23:23 --> 00:23:27 a delicate balance is disrupted because normally, 332 00:23:27 --> 00:23:31 let's say, a cell with have on its surface 500 EGF receptors, 333 00:23:31 --> 00:23:35 but in many kinds of cancers probably 30% or 40% of all 334 00:23:35 --> 00:23:39 carcinomas, carcinomas are the tumors from epithelial tissues, 335 00:23:39 --> 00:23:42 you'll find overexpressed EGF receptor. Well, 336 00:23:42 --> 00:23:46 why is that interesting? It's interesting for the following 337 00:23:46 --> 00:23:50 reason. I told you before that the activation of a receptor depends on 338 00:23:50 --> 00:23:54 its ligand to persuading two receptor subunits to come together 339 00:23:54 --> 00:23:58 and start firing, as we just discussed. 340 00:23:58 --> 00:24:01 But if now all of a sudden the cell contains large amounts of this 341 00:24:01 --> 00:24:04 growth being expressed, of the growth factor receptor being 342 00:24:04 --> 00:24:07 expressed on the surface, ten or a hundred times more than 343 00:24:07 --> 00:24:11 normal, then these growth factor receptors are going to be rather 344 00:24:11 --> 00:24:14 densely packed on the cell surface. And now they may just come together 345 00:24:14 --> 00:24:17 because they happen to bump into each other very frequently. 346 00:24:17 --> 00:24:21 They don't need the growth factor to pull them together just because 347 00:24:21 --> 00:24:24 there are so many of them. So, there's random interactions, 348 00:24:24 --> 00:24:27 random bumping together And these two growth factor 349 00:24:27 --> 00:24:31 receptors may just bump together and thereby send signals into the cell 350 00:24:31 --> 00:24:35 persuading the cell that there's been some kind of growth factor in 351 00:24:35 --> 00:24:39 the extracellular domain that's been encountered when, 352 00:24:39 --> 00:24:42 in fact, all that's happened is that there are so many of these growth 353 00:24:42 --> 00:24:46 factor receptors around that they're constantly bumping into each other, 354 00:24:46 --> 00:24:50 and while they've collided with one another they can activate signaling 355 00:24:50 --> 00:24:54 and release growth stimulatory signals into the cell. 356 00:24:54 --> 00:24:58 There's another kind of, of alteration of growth factor 357 00:24:58 --> 00:25:03 receptors that's also seen in many kinds of human tumors. 358 00:25:03 --> 00:25:08 For example, in, in glioblastomas, which is a brain tumor. And a 359 00:25:08 --> 00:25:13 glioblastoma has the following kind of, of receptor on the surface. 360 00:25:13 --> 00:25:18 It has truncated forms of the EGF receptor on the surface where a lot 361 00:25:18 --> 00:25:22 of the ectodomain is simply not present. So, here's the normal EGF 362 00:25:22 --> 00:25:27 receptor, here is a truncated EGF receptor where a lot of the 363 00:25:27 --> 00:25:32 extracellular domain, which I'm calling the ectodomain, 364 00:25:32 --> 00:25:37 has simply been lopped off. How has it be lopped off? 365 00:25:37 --> 00:25:41 Well, there's been a mutation it the gene which has, 366 00:25:41 --> 00:25:45 in effect, deleted segments in coding the N-terminus of the 367 00:25:45 --> 00:25:49 receptor protein, which normally sticks its head out 368 00:25:49 --> 00:25:54 of the cell. And now you have these truncated receptors. 369 00:25:54 --> 00:25:58 And such truncated EGF receptors are able to fire constitutively. 370 00:25:58 --> 00:26:02 Constitutively implies that these receptors are able to fire in a 371 00:26:02 --> 00:26:07 fashion that is no longer regulated by physiologic signals. 372 00:26:07 --> 00:26:10 It's a high steady rate. So now these receptor molecules, 373 00:26:10 --> 00:26:14 these truncated receptor molecules flood the cell with growth 374 00:26:14 --> 00:26:18 stimulatory signal and, for reasons that aren't really clear 375 00:26:18 --> 00:26:22 to this day, these two, these receptor, truncated receptor 376 00:26:22 --> 00:26:26 molecules can dimerize, they can come together even if 377 00:26:26 --> 00:26:30 there's no extracellular ligand present, even if there's no growth 378 00:26:30 --> 00:26:34 factor in the extracellular space. And we now realize, 379 00:26:34 --> 00:26:38 for example, that there are a variety of structurally altered 380 00:26:38 --> 00:26:42 receptors that fire constitutively into a cell in many kinds of human 381 00:26:42 --> 00:26:46 tumors. And in each case the cancer cell is deluded into thinking that 382 00:26:46 --> 00:26:50 some growth factor has been encountered out here when, 383 00:26:50 --> 00:26:54 in fact, there's not at all. Once again, what we see is a 384 00:26:54 --> 00:26:58 situation in which the cell, the cancer cell is being deluded 385 00:26:58 --> 00:27:03 into thinking there's growth factors present, extracellular space. 386 00:27:03 --> 00:27:07 None has been present at all. There have been a variety of drugs 387 00:27:07 --> 00:27:12 developed against, for example, lung cancer. 388 00:27:12 --> 00:27:17 And there are a variety of different kinds of lung cancers. 389 00:27:17 --> 00:27:22 One is called non-small cell lung carcinoma. We don't have to deal 390 00:27:22 --> 00:27:26 with the subsets of lung cancers. And it turned out, it turned out 391 00:27:26 --> 00:27:31 that one of these drugs, it's called Iressa, had very mixed 392 00:27:31 --> 00:27:38 effects on patients. 393 00:27:38 --> 00:27:42 In about 90% of these, of the class of lung cancers, 394 00:27:42 --> 00:27:47 patients that were treated, the drug Iressa, used over the last several 395 00:27:47 --> 00:27:51 years, had almost no effect on the tumor treatment and the patients 396 00:27:51 --> 00:27:56 continued to, to proceed to their death. It had, 397 00:27:56 --> 00:28:00 it really had no effect. But in 10%, in fact, there was some 398 00:28:00 --> 00:28:05 dramatic responses and tumors shrunk down. 399 00:28:05 --> 00:28:09 Now, normally a 10% response rate would be enough to cause a drug 400 00:28:09 --> 00:28:13 company to abandon all further development of the drug because it's 401 00:28:13 --> 00:28:17 just too low a response and who wants to take a drug where the 402 00:28:17 --> 00:28:21 chances of having a good response are as low as 10%? 403 00:28:21 --> 00:28:25 It's just not a good situation. But then some geneticists here in 404 00:28:25 --> 00:28:29 Boston, one group at the MGH and another over at the Dana Farber, 405 00:28:29 --> 00:28:33 began to look at the lung cancer cells that responded, 406 00:28:33 --> 00:28:37 i.e., from tumors of patients that responded and shrank in response to 407 00:28:37 --> 00:28:41 the drug and the lung, and the lung cancer cells of 408 00:28:41 --> 00:28:44 patients who didn't. It turns out that Iressa is an 409 00:28:44 --> 00:28:48 inhibitor of the tyrosine kinase of the EGF receptor. 410 00:28:48 --> 00:28:52 That's how it was designed. In other words, this drug, it's a 411 00:28:52 --> 00:28:56 low molecular weight drug and it goes into the tyrosine kinase domain, 412 00:28:56 --> 00:29:00 that rectangular thing I showed you before very schematically, 413 00:29:00 --> 00:29:04 and it shuts down the firing of the receptor. 414 00:29:04 --> 00:29:08 That was the motivation behind creating this drug. 415 00:29:08 --> 00:29:13 So, Iressa shuts down the EGF receptor and 10% of lung cancer 416 00:29:13 --> 00:29:18 patients, their tumor shrank, the other 90% didn't, weren't 417 00:29:18 --> 00:29:22 effected at all. And what these two groups of 418 00:29:22 --> 00:29:27 geneticists found over the last three or four months is that the 419 00:29:27 --> 00:29:32 patients whose tumors responded had tumor cells where the EGF receptor 420 00:29:32 --> 00:29:37 was mutated and therefore firing in a constitutively active fashion. 421 00:29:37 --> 00:29:40 That is to say there were actually structural alterations in the 422 00:29:40 --> 00:29:44 receptor. This is a massive structural alteration of the 423 00:29:44 --> 00:29:48 receptor here, this truncation. 424 00:29:48 --> 00:29:52 But, in fact, in certain patients the 10% of patients that responded, 425 00:29:52 --> 00:29:56 there were much more subtle changes in the cytoplasmic domain of the 426 00:29:56 --> 00:30:00 protein which allowed these receptors to constitutively dimerize, 427 00:30:00 --> 00:30:04 once again, in a ligand independent fashion. 428 00:30:04 --> 00:30:08 So, these subtle mutations mimic, in effect, the consequences of 429 00:30:08 --> 00:30:12 deleting or truncating the extracellular domain in that in both 430 00:30:12 --> 00:30:16 cases one gets a ligand independent receptor. In those cases where 431 00:30:16 --> 00:30:20 these, where the patients had a mutant EGF receptor, 432 00:30:20 --> 00:30:24 structurally altered EGF receptor that was firing constitutively, 433 00:30:24 --> 00:30:28 there were dramatic responses to the Iressa drug. 434 00:30:28 --> 00:30:31 In the 90% of patients where there was no effective response to the 435 00:30:31 --> 00:30:35 drug, the EGF receptor was wild-type, it was present in a wild-type 436 00:30:35 --> 00:30:39 configuration. It might have been slightly 437 00:30:39 --> 00:30:43 overexpressed but it wasn't, but it continued to, to function 438 00:30:43 --> 00:30:46 essentially as a normal EGF receptor. And this represents a major advance 439 00:30:46 --> 00:30:50 in cancer therapy because it suggests that one has to begin to 440 00:30:50 --> 00:30:54 understand what subsets of patients one should treat with a drug which 441 00:30:54 --> 00:30:58 can, on its own, have quite toxic effects on the 442 00:30:58 --> 00:31:01 patient. And, from now on, 443 00:31:01 --> 00:31:05 to state the obvious, when one gets lung cancer patients 444 00:31:05 --> 00:31:09 one will check quickly using various reactions, like the PCR reaction, 445 00:31:09 --> 00:31:13 to see whether or not their cancer cells have a mutated EGF receptor. 446 00:31:13 --> 00:31:16 And, if they do, they will be candidates for Iressa treatment with 447 00:31:16 --> 00:31:20 the expectation that 60%, 80% or even 100% of them will have 448 00:31:20 --> 00:31:24 tumors that respond. And if they don't have a mutated 449 00:31:24 --> 00:31:28 EGF receptor then they will not be subjected to a treatment 450 00:31:28 --> 00:31:31 by this drug. This is the beginning of a new era 451 00:31:31 --> 00:31:35 of cancer drug treatment. It's called rational drug design, 452 00:31:35 --> 00:31:39 or rational treatment, where you don't just lump all the patients 453 00:31:39 --> 00:31:43 with a certain disease together and say let's give them all this drug 454 00:31:43 --> 00:31:46 and throw things up in the air and see what happens. 455 00:31:46 --> 00:31:50 Here one begins to do a genetic diagnosis of the genomes of the 456 00:31:50 --> 00:31:54 patient's cancer cells in order to determine whether or not they have 457 00:31:54 --> 00:31:58 certain mutated genes. In this case we're referring to one 458 00:31:58 --> 00:32:02 of these growth factor receptors. By the way, we're talking about lung 459 00:32:02 --> 00:32:06 cancer today, right? If you are smoking now, 460 00:32:06 --> 00:32:10 I always ask the class how many people are smoking, 461 00:32:10 --> 00:32:14 and nobody has the, has the moral fortitude to raise their hands. 462 00:32:14 --> 00:32:18 But if you are smoking now and you started at this age and you continue. 463 00:32:18 --> 00:32:22 And, by the way, if you start at your age and you 464 00:32:22 --> 00:32:26 continue smoke, stopping smoking is actually a bit 465 00:32:26 --> 00:32:30 more difficult, quite a bit more difficult than 466 00:32:30 --> 00:32:34 stopping heroine. That's pretty interesting, 467 00:32:34 --> 00:32:38 right? So, if you continue to smoke now you will be healthy for a pretty 468 00:32:38 --> 00:32:42 long period of time, probably another 20 or 30 years. 469 00:32:42 --> 00:32:46 And for you that sounds like forever, but when you get to be 470 00:32:46 --> 00:32:50 about 40 or 50 things are going to start falling apart. 471 00:32:50 --> 00:32:54 Soon you won't be able to be very athletic, soon your lungs are going 472 00:32:54 --> 00:32:58 to be able, are going to degrade, and by the time you reach your 473 00:32:58 --> 00:33:02 fifties, sixties or seventies what's going to happen is you will, 474 00:33:02 --> 00:33:06 on average, have a six to eight year shortened life expectancy. 475 00:33:06 --> 00:33:09 Now you say six to eight years is not that much, 476 00:33:09 --> 00:33:13 but it really is. You know, when you get to be 70 and 477 00:33:13 --> 00:33:17 you think you're going to die next year or you're going to die in six 478 00:33:17 --> 00:33:20 or eight years it makes a big difference. Six to eight years is 479 00:33:20 --> 00:33:24 an enormous difference in life expectancy. 20% of all people who 480 00:33:24 --> 00:33:28 died last year in this country, 20% of all deaths came from 481 00:33:28 --> 00:33:32 cigarette smoking. Imagine that. And when you die from cigarette 482 00:33:32 --> 00:33:36 smokes, smoking sometimes you get lung cancer. There probably were, 483 00:33:36 --> 00:33:40 I think, 600,000 people who died from smoking last year. 484 00:33:40 --> 00:33:44 Six hundred thousand. There were 55,000 American soldiers who died in 485 00:33:44 --> 00:33:48 Vietnam in the whole war, there were 220,000 American soldiers 486 00:33:48 --> 00:33:52 who died in all of World War II, and last year in this, and there 487 00:33:52 --> 00:33:56 were 3,000, or 2, 00 people who died in the World 488 00:33:56 --> 00:34:00 Trade Center. All right? Got all those numbers? 489 00:34:00 --> 00:34:05 So, last year 600, 00 people died premature deaths 490 00:34:05 --> 00:34:10 because they were smoking. How many people died last year from 491 00:34:10 --> 00:34:15 smoking marijuana? Maybe two or three, 492 00:34:15 --> 00:34:20 I don't know. [APPLAUSE] Am I urging you to do any kind of smoking? 493 00:34:20 --> 00:34:25 I'm not saying marijuana smoking is good for you, but I just want you to 494 00:34:25 --> 00:34:30 get these things in mind, the perspective. 495 00:34:30 --> 00:34:33 If you smoke, you know, in many countries, including this 496 00:34:33 --> 00:34:37 one, there isn't much tension by, given by the government to, 497 00:34:37 --> 00:34:40 dissuading people from smoking, and here's the reason why. If you 498 00:34:40 --> 00:34:44 smoke, and you going to get, get sick eventually, eventually the 499 00:34:44 --> 00:34:47 country is always going to have to pay for your medical costs, 500 00:34:47 --> 00:34:51 right? Sooner or later we all have to pay for the costs of people who 501 00:34:51 --> 00:34:54 get sick. It's all shared in one way or another. 502 00:34:54 --> 00:34:58 But it's not such a big problem for a government like the 503 00:34:58 --> 00:35:02 American government. Because if you smoke you're going to 504 00:35:02 --> 00:35:06 die early enough that you won't draw on social security. 505 00:35:06 --> 00:35:10 And, therefore, the government actually saves money by your smoking, 506 00:35:10 --> 00:35:14 because by the time they add up how much they get on the tobacco tax and 507 00:35:14 --> 00:35:18 how much they earn by your not living long enough to draw a pension, 508 00:35:18 --> 00:35:22 it's much better, it's much more money than how much 509 00:35:22 --> 00:35:26 it's going to cost to take care of you while you're dying from 510 00:35:26 --> 00:35:30 emphysema or bladder cancer or lung cancer or heart disease. 511 00:35:30 --> 00:35:33 Many more people die from heart attacks due to smoking than die from 512 00:35:33 --> 00:35:37 lung cancer, in fact. So, think about this. 513 00:35:37 --> 00:35:41 Think about this. If you smoke it's probably a good time to stop 514 00:35:41 --> 00:35:45 because if you continue at your age, especially if you're women, which is 515 00:35:45 --> 00:35:48 women, for some reason women have a harder time stopping than men, 516 00:35:48 --> 00:35:52 they can't say why. It's probably some physiological thing. 517 00:35:52 --> 00:35:56 If you, if you continue now at your age, it will be almost impossible to 518 00:35:56 --> 00:36:00 stop. If you live with smokers ask them to leave. [LAUGHTER] 519 00:36:00 --> 00:36:04 If you live at home with your parents and they smoke tell them 520 00:36:04 --> 00:36:08 it's time for them to leave. Throw them out of the house. 521 00:36:08 --> 00:36:12 Smoke, second-hand smoking killed probably between 60, 522 00:36:12 --> 00:36:16 00 and 80,000 people last year in this country. Second-hand smoke. 523 00:36:16 --> 00:36:20 And, by the way, if you want to see an interesting phenomenon, 524 00:36:20 --> 00:36:24 go to a veterinary hospital because there they with great frequently, 525 00:36:24 --> 00:36:28 frequency treat dogs who have lung cancer. And why do they 526 00:36:28 --> 00:36:32 have lung cancer? Not in 99% of the cases, 527 00:36:32 --> 00:36:36 in 100% of the cases these dogs live with owners who smoke. 528 00:36:36 --> 00:36:40 An average tobacco smoker goes through six or eight dogs in his or 529 00:36:40 --> 00:36:44 her lifetime. [LAUGHTER] It's true. It's absolutely true. 530 00:36:44 --> 00:36:49 So if you, if you think the dogs, if that's a fact for the, for the, 531 00:36:49 --> 00:36:53 for the dog owners, think about what's happening to the 532 00:36:53 --> 00:36:57 inside of your lungs. And so I'm going to take back what 533 00:36:57 --> 00:37:02 I said before. Before I told you that the most 534 00:37:02 --> 00:37:06 important thing for you to do in this course is to learn how to think 535 00:37:06 --> 00:37:10 clearly and to assess and to distil conceptually complex material, 536 00:37:10 --> 00:37:14 there's actually one more thing that's even more important to get 537 00:37:14 --> 00:37:18 out of this course, if you do, and that is to stop 538 00:37:18 --> 00:37:22 smoking. If you do that, if you do that it'll be vastly more 539 00:37:22 --> 00:37:26 important for the rest of your life than anything you learn here. 540 00:37:26 --> 00:37:30 So, write that down, vastly more important. You may think it's 541 00:37:30 --> 00:37:34 glamorous, you may think it's exciting, but keep in mind, 542 00:37:34 --> 00:37:38 people who stop smoking have vastly greater effects on reducing the 543 00:37:38 --> 00:37:42 morbidity and the mortality in this country than anything that cancer 544 00:37:42 --> 00:37:46 researchers can do. Keep that in mind. 545 00:37:46 --> 00:37:50 And if you start smoking now and you think that somehow the cancer 546 00:37:50 --> 00:37:53 researchers are going to be able to come up with some miracle cure by 547 00:37:53 --> 00:37:56 this time you start coughing and start spitting up blood, 548 00:37:56 --> 00:38:00 don't be so certain. They may not be able to save you, 549 00:38:00 --> 00:38:04 to pull your fat out of the fire. So, I don't know whether I, 550 00:38:04 --> 00:38:08 I gave this message in a very subtle way or I hit you over the head with 551 00:38:08 --> 00:38:12 it. [LAUGHTER] But think, think about that. Now, now we're 552 00:38:12 --> 00:38:16 going to focus on lung cancer, we're going to focus on cancer 553 00:38:16 --> 00:38:20 because it's one of the consequences of cigarette smoking, 554 00:38:20 --> 00:38:24 but it's a disease we want to talk about both this time and next time, 555 00:38:24 --> 00:38:28 and we want to relate it here to the cell cycle and, 556 00:38:28 --> 00:38:32 and how the growth of cell proliferation occurs. 557 00:38:32 --> 00:38:36 I told you last time that a human tumor is roughly-speaking about, 558 00:38:36 --> 00:38:40 a human body roughly carries three times ten to the thirteenth cells. 559 00:38:40 --> 00:38:44 So, that's quite a few cells. That's how many cells there are in 560 00:38:44 --> 00:38:48 the human body, plus or minus. A human tumor of one, 561 00:38:48 --> 00:38:52 let's say one cubic centimeter is roughly ten to the ninth cells. 562 00:38:52 --> 00:38:56 So, a tiny tumor this way already has a billion cells in it. 563 00:38:56 --> 00:39:00 And what I want to say is that those billion cells, 564 00:39:00 --> 00:39:04 or if the tumor grows larger to ten to a hundred billion cells, 565 00:39:04 --> 00:39:09 it's still not that much compared with the overall size of the body. 566 00:39:09 --> 00:39:14 But tumors of that size can kill you. And one, an interesting and 567 00:39:14 --> 00:39:19 important thing to realize about all the cancer cells in that tumor mass 568 00:39:19 --> 00:39:24 is that they all descend from a single progenitor. 569 00:39:24 --> 00:39:29 In other words, if we imagine a situation where here are a whole 570 00:39:29 --> 00:39:34 bunch of normal cells and here's the boundary between normalcy up here 571 00:39:34 --> 00:39:40 and malignancy, malignancy obviously refers to 572 00:39:40 --> 00:39:45 cancer, we could imagine where there are many cells which independently 573 00:39:45 --> 00:39:50 cross the boundary from one to the other and become the progenitors of 574 00:39:50 --> 00:39:55 a vast tumor mass. But that's not what happens. 575 00:39:55 --> 00:40:00 What happens, in fact, is that only one cell gets converted or becomes, 576 00:40:00 --> 00:40:05 as one says here, it becomes transformed from a normal cell into 577 00:40:05 --> 00:40:10 a cancer cell. And this transformation causes this 578 00:40:10 --> 00:40:15 one cell to become the progenitor, the ancestor of all the cells in the 579 00:40:15 --> 00:40:20 tumor mass. So, one important realization we have 580 00:40:20 --> 00:40:25 about looking at different tumors is that cancers are monoclonal growths, 581 00:40:25 --> 00:40:30 i.e., they form clonal populations. They're monoclonal in the sense that 582 00:40:30 --> 00:40:35 they all are genetically derived from a single common ancestor rather 583 00:40:35 --> 00:40:40 than being polyclonal. What else can we say about cancer 584 00:40:40 --> 00:40:44 cells or the cells in a tumor? If you take cells out of Petri dish, 585 00:40:44 --> 00:40:48 out of an animal or a human and put them on a Petri dish, 586 00:40:48 --> 00:40:52 excuse me, and you put them there, then what you'll see is following 587 00:40:52 --> 00:40:56 interesting behavior. If you put normal cells in a Petri 588 00:40:56 --> 00:41:00 dish they'll grow across the bottom of the Petri dish until they cover 589 00:41:00 --> 00:41:04 the entire bottom of the Petri dish. 590 00:41:04 --> 00:41:08 So, you can put a hundred cells in and they'll continue to proliferate. 591 00:41:08 --> 00:41:12 Let's look at the Petri dish from top down, so you might have a small 592 00:41:12 --> 00:41:16 number of cells here and here, and normal cells will continue to 593 00:41:16 --> 00:41:21 proliferate until they begin to touch one another, 594 00:41:21 --> 00:41:25 and then they'll stop growing. And this stopping of growing is, 595 00:41:25 --> 00:41:30 is the phenomenon that's called contact inhibition. 596 00:41:30 --> 00:41:33 So, a normal cell will indicate contact inhibition. 597 00:41:33 --> 00:41:37 And to state, to state the obvious, this phenomenon or this behavior of 598 00:41:37 --> 00:41:40 contact inhibition creates what's called a cell monolayer because if 599 00:41:40 --> 00:41:44 the cell stopped growing once they touch each other they're not going 600 00:41:44 --> 00:41:47 to be two or three or four layers of cells in the Petri dish. 601 00:41:47 --> 00:41:51 So, here we're looking at this Petri dish in cross-section and 602 00:41:51 --> 00:41:55 there's a monolayer of normal cells here. 603 00:41:55 --> 00:41:58 If you put a cancer cell in the Petri dish, or let's put here a 604 00:41:58 --> 00:42:02 cancer cell, we'll seed it amidst normal cells, what will happen is 605 00:42:02 --> 00:42:06 that the cancer cell lacks, has lost contact inhibition, 606 00:42:06 --> 00:42:09 and the cancer cell will continue to proliferate even after it's touched 607 00:42:09 --> 00:42:13 its neighbors. So, it has lost cancer, 608 00:42:13 --> 00:42:17 it has lost contact inhibition and will start growing on top of, 609 00:42:17 --> 00:42:20 the cancer cells will start growing on top of each other because they 610 00:42:20 --> 00:42:24 don't mind growing in spite of their having intimate contact with 611 00:42:24 --> 00:42:28 neighboring cells. And, in fact, what you can do is 612 00:42:28 --> 00:42:32 the following experiment. You can put cells in a Petri dish 613 00:42:32 --> 00:42:37 like this, a whole bunch of normal cells in a Petri dish, 614 00:42:37 --> 00:42:42 and then you can put into them some kind of transforming influence, 615 00:42:42 --> 00:42:47 which we'll talk about very shortly, i.e., you can influence some of 616 00:42:47 --> 00:42:52 these cells to become transformed. And how we do so we'll tell, we'll 617 00:42:52 --> 00:42:57 hold in abeyance just for a moment. So, we'll have this cell. We'll do 618 00:42:57 --> 00:43:02 this cell to become transformed and this cell to become transformed. 619 00:43:02 --> 00:43:05 And what will happen is that those cells will begin to form a very 620 00:43:05 --> 00:43:09 thick clump of cells, these blue ones, the ones that are 621 00:43:09 --> 00:43:13 transformed. Whereas, all the other cells will grow until 622 00:43:13 --> 00:43:16 they form a monolayer at which point they'll stop proliferating. 623 00:43:16 --> 00:43:20 So, the cancer cells keep piling up and the transformed cells, 624 00:43:20 --> 00:43:24 transformed by one or another agent, we won't talk about that yet, 625 00:43:24 --> 00:43:28 continue to proliferate long after the normal cells have stopped 626 00:43:28 --> 00:43:31 proliferating. The normal cells having stopped 627 00:43:31 --> 00:43:35 proliferating because they're contact inhibited. 628 00:43:35 --> 00:43:38 And, therefore, they'll form this clump of cells which we'll call a 629 00:43:38 --> 00:43:42 focus. And if you hold the Petri dish up to the light and you look at 630 00:43:42 --> 00:43:45 it and there are some transformed cells present, 631 00:43:45 --> 00:43:49 you can see the foci, they're very thick. Whereas, 632 00:43:49 --> 00:43:52 the thin monolayer of cells will just look pretty transparent. 633 00:43:52 --> 00:43:56 But this focus will look highly opaque by virtue of the multiple 634 00:43:56 --> 00:44:00 layers of cells that are involved in it. 635 00:44:00 --> 00:44:05 Now, in fact, we can begin to ask the question of how and why cells 636 00:44:05 --> 00:44:10 like this become transformed and exhibit this behavior. 637 00:44:10 --> 00:44:16 In fact, until the 1980s there wasn't really a clear understanding 638 00:44:16 --> 00:44:21 about how that happened. I've already given you some clues 639 00:44:21 --> 00:44:27 because I've already told you the fact that certain cancer cells carry 640 00:44:27 --> 00:44:32 mutant genes. What kind of mutant genes? 641 00:44:32 --> 00:44:36 Well, I gave you, in anticipation of discussion, 642 00:44:36 --> 00:44:40 the fact that certain cancer cells carry mutant genes that specify 643 00:44:40 --> 00:44:44 mutant growth factor receptors. And these mutant growth factor 644 00:44:44 --> 00:44:49 receptors, as I indicated, begin to push the cell the 645 00:44:49 --> 00:44:53 proliferate. And so that already anticipates a conclusion we're about 646 00:44:53 --> 00:44:57 to make, which is that the reason why cancer cells behave abnormally 647 00:44:57 --> 00:45:02 is that they carry mutant genes. Now, let's talk about the nature of 648 00:45:02 --> 00:45:07 these mutant genes because, if you look at these mutant genes, 649 00:45:07 --> 00:45:12 invariably they are the consequences of what we call somatic mutations. 650 00:45:12 --> 00:45:17 By that I mean, I mean the following. Let's say we all start 651 00:45:17 --> 00:45:22 out with a really good set of genes. And, thank the good Lord, we all do. 652 00:45:22 --> 00:45:27 But as we go through life through accidents or through intent we can 653 00:45:27 --> 00:45:32 damage these genes. We can muck them up in different 654 00:45:32 --> 00:45:36 ways. And these genes, this damage may occur to cells in 655 00:45:36 --> 00:45:41 the skin, they may occur to cells in your belly, they may occur to cells 656 00:45:41 --> 00:45:45 in the brain, and these are called somatic mutations in contrast to the 657 00:45:45 --> 00:45:50 germline mutations that affect one's offspring. Because, 658 00:45:50 --> 00:45:54 as you must realize by now, the only way you can have mutations 659 00:45:54 --> 00:45:59 that affect your descendents is if those mutations strike in the gonads 660 00:45:59 --> 00:46:04 and affect the genomes of either sperm or egg. 661 00:46:04 --> 00:46:08 But the mutations occurring everywhere else in the body outside 662 00:46:08 --> 00:46:12 of the gonads, because they occur in, 663 00:46:12 --> 00:46:16 I think I, this is somatic, excuse me, because they occur in the 664 00:46:16 --> 00:46:21 soma, the soma is defined as the entirety of the body outside of the 665 00:46:21 --> 00:46:25 gonads, outside of the germi, these somatic mutations might affect 666 00:46:25 --> 00:46:29 the tissues around them but they will not be transmitted from one 667 00:46:29 --> 00:46:34 organismic generation to the next. And, accordingly, 668 00:46:34 --> 00:46:38 we begin to imagine, in fact, correctly we begin to 669 00:46:38 --> 00:46:42 construct this model that one of the most important mechanisms of 670 00:46:42 --> 00:46:46 creating a cancer cell is to damage its genome. So, 671 00:46:46 --> 00:46:50 I'll tell you a story now, which I'm only going to finish on 672 00:46:50 --> 00:46:54 Monday. We have, let's imagine, a 55-year-old, 673 00:46:54 --> 00:46:58 this is a true story, 55-year-old man who's been smoking since he or 674 00:46:58 --> 00:47:02 she, he was 15 years old. So, he's been smoking for 40 years. 675 00:47:02 --> 00:47:06 And during those periods of 40 years, by the way, I'm not saying whether 676 00:47:06 --> 00:47:10 I'm for or against smoking, you understand that. During that 677 00:47:10 --> 00:47:15 period of 40 years this person has been introducing large amounts of 678 00:47:15 --> 00:47:19 tobacco smoke compounds into his lungs. Now, it turns out that these 679 00:47:19 --> 00:47:23 compounds, this tobacco smoke compounds are carcinogens. 680 00:47:23 --> 00:47:28 You know carcinogen means it causes cancer. But it happens also to be 681 00:47:28 --> 00:47:32 the case that a lot of carcinogens, cancer-causing compounds are also 682 00:47:32 --> 00:47:37 mutagens. That is to say they can mutate DNA. 683 00:47:37 --> 00:47:41 So, here we have a scenario that we're going to set up for next time. 684 00:47:41 --> 00:47:46 55-year-old man. Smokes for 40 years. Dumps a lot of carcinogens 685 00:47:46 --> 00:47:50 into his lungs. The carcinogens which are highly, 686 00:47:50 --> 00:47:55 which induce mutations very potently are passed from his lungs into his 687 00:47:55 --> 00:48:00 blood and there go from the blood into the kidneys. 688 00:48:00 --> 00:48:04 And from the kidneys they are excreted into the urine and then 689 00:48:04 --> 00:48:09 they sit around in the bladder for a while. And let's imagine now that 690 00:48:09 --> 00:48:13 the urine of this man has all of these highly mutation-active 691 00:48:13 --> 00:48:18 carcinogens in his urine, which, in principle, can begin now 692 00:48:18 --> 00:48:23 to strike out and attack the genomes of the cells lining the urinary 693 00:48:23 --> 00:48:27 bladder. In other words, by, by smoking cigarettes you can 694 00:48:27 --> 00:48:32 actually mutate the genomes, somatic mutation, the genomes of 695 00:48:32 --> 00:48:37 cells lining the bladder of the, the urinary bladder, or, of course, 696 00:48:37 --> 00:48:41 to state the obvious, you can also mutate the genomes of the cells 697 00:48:41 --> 00:48:46 lining the alveoli in the lungs. That's why you get lung cancer. 698 00:48:46 --> 00:48:50 And a consequence of this can be, with serious probability, that now 699 00:48:50 --> 00:48:54 some of these cells become mutated and that, in turn, 700 00:48:54 --> 00:48:58 will lead to a life-threatening tumor. So, on this very cheerful 701 00:48:58 --> 00:49:02 note and your having heard two major take-home lessons, have 702 00:49:02 --> 00:49:07 a great weekend. See you on Monday. Enjoy 703 00:49:07 --> 49:12 the parade tomorrow.