1 00:00:05,049 --> 00:00:08,159 Jen: Welcome to the So That's Why podcast, where we unpack the 2 00:00:08,159 --> 00:00:10,129 science behind everyday questions. 3 00:00:10,159 --> 00:00:10,780 I'm Jen. 4 00:00:11,049 --> 00:00:11,659 Chris: I'm Chris. 5 00:00:12,019 --> 00:00:12,709 Matt: And I'm Matt. 6 00:00:13,299 --> 00:00:17,000 Jen: So before we start, a quick heads-up about today. 7 00:00:17,189 --> 00:00:21,339 Today is about the biology, what physically changes inside 8 00:00:21,339 --> 00:00:23,269 a cell to turn it cancerous. 9 00:00:23,549 --> 00:00:28,369 So we're not gonna be looking at causes, risk, or anyone's diagnosis. 10 00:00:28,370 --> 00:00:32,340 So if this is a heavy subject for you right now, it's completely 11 00:00:32,340 --> 00:00:34,049 okay to sit this one out. 12 00:00:34,259 --> 00:00:36,629 Chris: Yeah, and I think it feels important to say that plainly, doesn't it? 13 00:00:36,639 --> 00:00:38,529 Mm. Because cancer really is a heavy topic. 14 00:00:38,529 --> 00:00:38,919 Mm-hmm. 15 00:00:39,069 --> 00:00:42,549 But it's something we get asked about all the time, so today we're aiming 16 00:00:42,550 --> 00:00:46,509 to get stuck into the science, really because the related cell biology 17 00:00:46,709 --> 00:00:50,389 itself is one of the most extraordinary stories the body has to tell. 18 00:00:51,169 --> 00:00:54,710 Matt: Which is good, because I'll be honest, this is one of those topics I've 19 00:00:54,719 --> 00:00:58,449 steered away from, uh, a little bit, and a lot of people, I think, do the same. 20 00:00:58,449 --> 00:01:01,409 It feels like a massive topic, doesn't it? 21 00:01:01,719 --> 00:01:05,589 Jen: Yeah, and I think that's really honest, and it's part 22 00:01:05,589 --> 00:01:06,889 of why we wanted to do it. 23 00:01:07,179 --> 00:01:08,389 So here's the question. 24 00:01:08,589 --> 00:01:14,729 Your body will make tens of billions of new cells today alone, and to 25 00:01:14,730 --> 00:01:19,949 make each one, it copies three billion letters of DNA, and almost 26 00:01:19,989 --> 00:01:22,329 every copy comes out flawless. 27 00:01:22,579 --> 00:01:25,899 So the real puzzle isn't why cells sometimes go wrong, 28 00:01:25,969 --> 00:01:28,210 it's why they so rarely do. 29 00:01:28,579 --> 00:01:31,649 But why do cells turn cancerous? 30 00:01:32,300 --> 00:01:34,439 Chris: Yeah, and I think before getting into it, that scale you 31 00:01:34,439 --> 00:01:37,100 mentioned there, Jen, is like, it's so important to keep in mind. 32 00:01:37,109 --> 00:01:42,189 So over a lifetime, that's tens of trillions of cell divisions, each one 33 00:01:42,259 --> 00:01:46,079 copying what's effectively a three billion letter instruction manual. 34 00:01:46,319 --> 00:01:47,489 Matt: Which is crazy. 35 00:01:47,629 --> 00:01:47,849 Jen: Yeah. 36 00:01:48,619 --> 00:01:48,913 Can't get your head around it 37 00:01:48,913 --> 00:01:49,077 Matt: at all. 38 00:01:49,077 --> 00:01:49,160 Right. 39 00:01:49,160 --> 00:01:51,349 I mean, that would take a supercomputer, uh- 40 00:01:51,359 --> 00:01:51,849 Jen: Yeah 41 00:01:52,069 --> 00:01:55,900 … Matt: so, uh, uh, 'cause my body, like, is doing this sort of copy job, isn't it? 42 00:01:55,900 --> 00:02:00,589 This sort of big copying, and it's mostly getting it right- Mm … which 43 00:02:00,590 --> 00:02:04,350 is, I mean, I can't copy a phone number without messing up a few of the digits, 44 00:02:04,359 --> 00:02:06,459 so how my body does this, I have no idea. 45 00:02:06,539 --> 00:02:06,869 Jen: I know. 46 00:02:06,879 --> 00:02:07,959 Honestly, I'm the same. 47 00:02:09,209 --> 00:02:11,559 But you know, that's the, it's the right instinct. 48 00:02:11,579 --> 00:02:13,539 So errors do happen. 49 00:02:13,829 --> 00:02:18,359 Um, but the remarkable part is actually how much proofreading and 50 00:02:18,359 --> 00:02:22,909 repair sits on top of it all to catch them before they even matter. 51 00:02:23,329 --> 00:02:25,869 Chris: Which, let's be honest, this is really what it all comes down to. 52 00:02:25,869 --> 00:02:28,309 So cancer isn't one dramatic event. 53 00:02:28,789 --> 00:02:31,570 It's what happens on the very rare occasions- Mm-hmm … where a 54 00:02:31,799 --> 00:02:35,469 series of those safeguards fail in the same cell one after another. 55 00:02:36,079 --> 00:02:40,130 Jen: Okay, so let's start with what a normal cell does, because you can't see 56 00:02:40,130 --> 00:02:42,239 what's broken until you know the rules. 57 00:02:42,500 --> 00:02:46,299 So a healthy cell only divides when it's signaled to. 58 00:02:46,529 --> 00:02:51,599 It does its specific job, and here's the one people forget or maybe don't know. 59 00:02:51,929 --> 00:02:53,729 It dies on a schedule too. 60 00:02:54,109 --> 00:02:58,089 Matt: So so my cells are programmed to die. 61 00:02:58,129 --> 00:02:58,549 Jen: Mm-hmm. 62 00:02:59,190 --> 00:03:01,379 Matt: Sounds a little bit like a fault, not a feature. 63 00:03:01,379 --> 00:03:01,709 Not gonna lie. 64 00:03:02,369 --> 00:03:05,657 Chris: Actually the opposite of a fault, and it's called apoptosis, 65 00:03:05,677 --> 00:03:09,397 which is a controlled self-shutdown the body uses to constantly clear 66 00:03:09,397 --> 00:03:13,427 out cells that are old, that are damaged, or that are no longer needed. 67 00:03:14,007 --> 00:03:15,877 Matt: So apoptosis. 68 00:03:16,307 --> 00:03:16,387 Well done. 69 00:03:16,397 --> 00:03:17,537 Sounds like a pop group, isn't it? 70 00:03:17,537 --> 00:03:17,547 It 71 00:03:17,547 --> 00:03:17,897 Jen: does. 72 00:03:18,757 --> 00:03:19,287 Matt: Apoptosis. 73 00:03:19,727 --> 00:03:25,287 Is a cell then doing the responsible thing and stepping aside when it's supposed to? 74 00:03:25,927 --> 00:03:30,597 Jen: Yep, and that's the deal that a cancer cell breaks, so it stops obeying 75 00:03:30,657 --> 00:03:35,257 any of those rules, not because anything invades from the outside, but because 76 00:03:35,277 --> 00:03:38,057 its own DNA instructions get rewritten. 77 00:03:38,497 --> 00:03:38,957 Chris: That's it. 78 00:03:39,007 --> 00:03:43,417 And, uh, to see how that rewriting happens, I think it helps to know 79 00:03:43,607 --> 00:03:47,087 what the instructions are made of and how they get copied, doesn't it? 80 00:03:47,817 --> 00:03:48,087 Matt: Yeah. 81 00:03:48,087 --> 00:03:53,307 Well, go on then, because DNA is one of those words I use confidently- … uh, 82 00:03:53,317 --> 00:03:57,367 but cannot really ever explain, and don't ask me what it stands for. 83 00:03:57,367 --> 00:03:58,217 I just would not know. 84 00:03:58,947 --> 00:04:00,237 Jen: So most people are the same. 85 00:04:00,957 --> 00:04:01,387 Okay. 86 00:04:01,417 --> 00:04:04,757 So DNA, deoxyribonucleic acid. 87 00:04:04,907 --> 00:04:05,757 Matt: You're just showing off now, 88 00:04:05,757 --> 00:04:05,827 Jen: aren't you? 89 00:04:05,827 --> 00:04:06,417 Yeah, I am. 90 00:04:07,997 --> 00:04:09,397 Chris: We can ask you to, uh, pronounce that at the end. 91 00:04:09,397 --> 00:04:09,627 Yeah, yeah, 92 00:04:09,627 --> 00:04:11,727 Matt: yeah. 93 00:04:11,727 --> 00:04:16,097 Jen: It's a long instruction written in a four-letter alphabet. 94 00:04:16,357 --> 00:04:21,077 So you've got A, T, C, and G, and they're also called bases, 95 00:04:21,107 --> 00:04:23,977 and they pair up in a fixed way. 96 00:04:23,987 --> 00:04:28,217 So A always bonds with T, and C always bonds with G. 97 00:04:28,757 --> 00:04:32,457 Matt: So it's two matching halves, and each half tells you 98 00:04:32,457 --> 00:04:33,827 what the other one should say? 99 00:04:33,887 --> 00:04:34,277 Jen: Mm-hmm. 100 00:04:34,447 --> 00:04:36,187 Chris: Yep, and that's what makes the copying possible. 101 00:04:36,197 --> 00:04:39,627 So you might have seen the classic DNA double helix structure. 102 00:04:39,737 --> 00:04:40,027 Matt: Mm-hmm. 103 00:04:40,407 --> 00:04:44,987 Chris: And when a cell divides, that double helix basically unzips, uh, 104 00:04:44,987 --> 00:04:47,857 down the middle, and each strand is used as a template to rebuild 105 00:04:47,857 --> 00:04:49,627 its partner one letter at a time. 106 00:04:50,367 --> 00:04:53,107 Matt: So the pairing rule is a built-in check then. 107 00:04:53,167 --> 00:04:58,597 If one side reads A, the new partner has got to be a T or something's gone wrong. 108 00:04:58,797 --> 00:05:02,507 Jen: Yeah, and that check, it's why, it's why most of the errors get caught. 109 00:05:02,967 --> 00:05:07,977 But across three billion letters, some slip through, and they 110 00:05:08,007 --> 00:05:09,387 come in three different kinds. 111 00:05:09,397 --> 00:05:13,167 So you can have them where a letter can b- can be substituted for the 112 00:05:13,167 --> 00:05:18,397 wrong one, or an extra letter can be inserted, or one can be deleted. 113 00:05:18,747 --> 00:05:22,457 Matt: Okay, and I'm guessing, and, you know, the magic scientist that I am, 114 00:05:22,767 --> 00:05:27,597 that an insertion or a deletion does more damage maybe than a straight swap. 115 00:05:28,257 --> 00:05:30,817 Chris: Well, you get a science point there, Matt, 'cause yes, usually. 116 00:05:30,857 --> 00:05:34,907 And it's because, um, DNA code is read in three letter blocks, and 117 00:05:34,907 --> 00:05:37,097 each block codes for one amino acid. 118 00:05:37,187 --> 00:05:40,837 And an amino acid, as you may know, is a building block of a protein. 119 00:05:41,417 --> 00:05:46,087 So if you substitute one letter, you can often change just a single block. 120 00:05:46,467 --> 00:05:51,321 But if you insert or delete one Every block after that shifts along by 121 00:05:51,321 --> 00:05:53,181 one, and it's called a frame shift. 122 00:05:53,331 --> 00:05:57,091 And basically from that point, the rest of the instruction reads as nonsense. 123 00:05:57,601 --> 00:05:58,701 Matt: A frame shift. 124 00:05:58,711 --> 00:05:59,621 Mm. Love that phrase. 125 00:05:59,861 --> 00:06:04,161 So a substitution is a typo in one word, but an insertion or 126 00:06:04,161 --> 00:06:07,871 deletion knocks the whole sentence out of step from that point on. 127 00:06:08,101 --> 00:06:08,531 Jen: Right. 128 00:06:08,651 --> 00:06:13,081 And any of those, like a substitution, an insertion, or a deletion, is 129 00:06:13,111 --> 00:06:17,651 what we mean by a mutation, and that is a permanent change to the 130 00:06:17,651 --> 00:06:19,801 DNA sequence in that one cell. 131 00:06:20,071 --> 00:06:25,531 Matt: Okay, so if these slip through, then often, three billion, uh, why 132 00:06:25,531 --> 00:06:27,101 aren't we constantly in trouble? 133 00:06:27,441 --> 00:06:30,891 Jen: Because the vast majority are harmless, so they'll land in stretches 134 00:06:30,891 --> 00:06:35,401 of DNA that don't actually code for anything, or they get repaired within 135 00:06:35,411 --> 00:06:37,781 minutes, or the cell triggers apoptosis. 136 00:06:38,701 --> 00:06:43,711 So a mutation, it only starts to matter when it hits one particular kind of gene. 137 00:06:44,001 --> 00:06:45,801 Chris: Yeah, and that's such an important thing to remember, isn't it? 138 00:06:45,871 --> 00:06:47,561 To kind of put it into context. 139 00:06:48,091 --> 00:06:52,341 Um, so there are two key families that count here, and the first is what 140 00:06:52,341 --> 00:06:57,611 we, we call, um, proto-oncogenes, and they normally drive healthy growth. 141 00:06:57,691 --> 00:07:01,511 So they tell cells to divide when there's a real signal. 142 00:07:01,851 --> 00:07:05,611 However, when you mutate one of those proto-oncogenes, it becomes 143 00:07:05,611 --> 00:07:10,491 an oncogene, meaning it's locked permanently on, so the cells divide 144 00:07:10,491 --> 00:07:12,661 nonstop even if there's no signal at all. 145 00:07:12,751 --> 00:07:13,071 Matt: Mm. 146 00:07:13,421 --> 00:07:18,311 So the gene whose whole job it is to say, "Grow," gets stuck in the in the 147 00:07:18,311 --> 00:07:22,071 forward position, in the on position, still shouting, "Grow," when nothing 148 00:07:22,071 --> 00:07:23,631 is actually asking it to, I'm guessing. 149 00:07:23,801 --> 00:07:28,291 Jen: Yeah, stuck, shouting, "Grow." Um, so you mentioned one family. 150 00:07:28,291 --> 00:07:31,411 The second family is a tumor suppressor gene. 151 00:07:31,661 --> 00:07:33,351 So they do the opposite job. 152 00:07:33,621 --> 00:07:38,891 They hold growth back, um, repairing DNA and calling for apoptosis 153 00:07:38,911 --> 00:07:40,361 when a cell is too far gone. 154 00:07:40,561 --> 00:07:43,081 But in cancer, those get switched off. 155 00:07:43,391 --> 00:07:46,521 Chris: They do, and the most important tumor suppressor is one you probably 156 00:07:46,521 --> 00:07:50,011 heard us talking about elsewhere, and it's P53, which is also nicknamed 157 00:07:50,011 --> 00:07:51,851 the, the Guardian of the Genome. 158 00:07:51,881 --> 00:07:54,961 Jen: Feel like I wanna salute it when you say Guardian of the Genome. 159 00:07:55,241 --> 00:07:57,221 Chris: Well, it's important enough, I think it, it, it deserves it. 160 00:07:57,281 --> 00:07:57,301 Yeah. 161 00:07:57,301 --> 00:08:03,031 Because when DNA's damaged, uh, P53 either halts the cell so it can be repaired, 162 00:08:03,381 --> 00:08:07,801 or if it's beyond saving, it orders that apoptosis, well, that cell death. 163 00:08:08,381 --> 00:08:12,281 And P53 is faulty in more than half of all cancers. 164 00:08:12,361 --> 00:08:12,761 Matt: Mm. 165 00:08:12,771 --> 00:08:19,001 So losing then P53 doesn't, uh, just allow damage, it removes the very thing 166 00:08:19,001 --> 00:08:20,981 that would have caught the damage. 167 00:08:21,241 --> 00:08:24,351 So it feels like a double blow when 53's not doing its job. 168 00:08:24,431 --> 00:08:24,791 Mm. 169 00:08:25,161 --> 00:08:27,841 Chris: It really is, and this is why it takes so long. 170 00:08:27,841 --> 00:08:31,851 So a cancer cell can carry hundreds of mutations, but most of them are 171 00:08:31,851 --> 00:08:34,921 passengers, so just effectively along for the ride doing nothing. 172 00:08:35,427 --> 00:08:38,867 It's that handful of driving mutations that matter, and it usually 173 00:08:38,907 --> 00:08:43,427 takes, uh, six or more distinct drivers stacking up in one cell 174 00:08:43,427 --> 00:08:45,217 line to kind of do the main damage. 175 00:08:45,777 --> 00:08:49,097 Jen: And there's a detail on the tumor suppressors worth having. 176 00:08:49,117 --> 00:08:53,937 So you inherit two copies of each, so both have to be knocked out 177 00:08:53,957 --> 00:08:56,687 before that safeguard is truly gone. 178 00:08:57,027 --> 00:09:02,027 It's called the two-hit rule, and it was first worked out in 1971 by 179 00:09:02,027 --> 00:09:04,207 a scientist called Alfred Knudsen. 180 00:09:04,477 --> 00:09:05,377 Matt: Not Alfred? 181 00:09:05,507 --> 00:09:06,687 Jen: Yeah, Alfred. 182 00:09:07,957 --> 00:09:08,097 Matt: Okay. 183 00:09:08,147 --> 00:09:08,357 RL. 184 00:09:08,357 --> 00:09:09,677 So RL. 185 00:09:09,677 --> 00:09:09,927 Yeah. 186 00:09:10,557 --> 00:09:14,127 So that's why I guess some tumor … uh, some cancers may 187 00:09:14,127 --> 00:09:15,347 be run in families, I'm guessing. 188 00:09:15,347 --> 00:09:20,527 If you're born already missing one copy- Mm … you only really need the 189 00:09:20,527 --> 00:09:24,647 second hit rather than the two, and you maybe are a step closer to the edge. 190 00:09:25,047 --> 00:09:28,177 Chris: Yeah, it's true, but I think it's really important to say it doesn't mean 191 00:09:28,177 --> 00:09:30,287 anyone's fate is sealed because of that. 192 00:09:30,457 --> 00:09:32,557 It just means that the count starts from a different place. 193 00:09:33,007 --> 00:09:33,357 Jen: Yeah. 194 00:09:33,907 --> 00:09:37,687 And once a few drivers are in, it can start to accelerate because some 195 00:09:37,687 --> 00:09:42,347 of the genes that get knocked out are the DNA repair genes themselves. 196 00:09:42,547 --> 00:09:43,057 Matt: Okay. 197 00:09:43,057 --> 00:09:44,877 I don't … I'm not sure I like where this is going. 198 00:09:45,107 --> 00:09:49,697 So once the proofreaders are gone, the errors, I'm assuming, then pile up faster. 199 00:09:50,117 --> 00:09:52,137 Chris: Yeah, and that's the honest, and I think fair to say, 200 00:09:52,257 --> 00:09:53,187 the unfortunate picture here. 201 00:09:53,427 --> 00:09:56,777 Mm. Because the whole genome in that situation becomes unstable. 202 00:09:57,157 --> 00:10:02,097 It's what's called a mutator phenotype, so more drivers arrive sooner, 203 00:10:02,487 --> 00:10:05,367 and the process that crept along for years can appear to speed up. 204 00:10:06,413 --> 00:10:08,593 Matt: Which reframes something for me, I guess. 205 00:10:08,593 --> 00:10:14,243 So when people say cancer appeared suddenly, it probably wasn't sudden. 206 00:10:14,243 --> 00:10:17,703 It had been building up maybe for a long time, and it just sort of 207 00:10:17,703 --> 00:10:20,043 crossed the, a line late on perhaps. 208 00:10:20,093 --> 00:10:22,163 Jen: Yeah, it's true for a lot of cancers. 209 00:10:22,363 --> 00:10:27,363 What looks sudden is usually the visible end of a long, quiet process. 210 00:10:27,373 --> 00:10:28,263 Chris: Yeah, that's right. 211 00:10:28,803 --> 00:10:33,063 And, um, moving around, there's one more layer worth talking about, but I will 212 00:10:33,063 --> 00:10:35,903 be up front that it's, it's newer, and it's still kind of developing in cancer 213 00:10:35,913 --> 00:10:41,413 research, and this is the concept that cells can also silence genes without 214 00:10:41,413 --> 00:10:43,223 changing the DNA letters at all. 215 00:10:43,803 --> 00:10:46,993 Matt: Hang on, so you can switch a gene off without editing it. 216 00:10:47,393 --> 00:10:48,583 How does that work? 217 00:10:48,613 --> 00:10:52,193 Jen: So the main route is a chemical tag called methylation. 218 00:10:52,203 --> 00:10:57,193 So the cell adds a methyl group to a gene's control region, and it goes quiet. 219 00:10:57,413 --> 00:10:59,623 So not one letter is changed. 220 00:10:59,633 --> 00:11:02,983 The instruction's still there, the cell just can't read it. 221 00:11:03,283 --> 00:11:09,043 And in cancer, that can switch off those same tumor suppressor and repair genes. 222 00:11:09,743 --> 00:11:14,473 Matt: So you get the same result as a mutation, an off switch, but with nothing 223 00:11:14,473 --> 00:11:16,383 you could spot in the sequence itself? 224 00:11:17,273 --> 00:11:17,823 Chris: Broadly, yeah. 225 00:11:18,193 --> 00:11:21,123 And, um, yeah, it's quite incredible really, isn't it? 226 00:11:21,223 --> 00:11:22,813 Mm. Not, not necessarily in a positive way. 227 00:11:22,933 --> 00:11:23,223 Jen: No. 228 00:11:23,303 --> 00:11:25,673 Chris: Uh, but, you know, I'll stress again, this is, this 229 00:11:25,673 --> 00:11:28,433 research is still maturing, but it's clearly part of the picture. 230 00:11:28,993 --> 00:11:31,843 Um, but it's fair to say, you know, it's a layer that we understand less 231 00:11:31,843 --> 00:11:33,483 completely than the mutation point. 232 00:11:34,203 --> 00:11:35,523 Jen: Mm-hmm. 233 00:11:35,523 --> 00:11:38,933 And it's worth also saying cancer isn't one thing, so it's a family of diseases 234 00:11:38,983 --> 00:11:44,643 in different tissues that share the same story, which is part of why no 235 00:11:44,673 --> 00:11:46,763 single treatment fits all of them. 236 00:11:47,123 --> 00:11:51,533 Matt: So even a single tumor, I'm guessing, isn't all identical cells? 237 00:11:52,143 --> 00:11:52,583 Chris: Correct. 238 00:11:52,603 --> 00:11:53,823 That's usually not the case. 239 00:11:53,863 --> 00:11:58,073 Um, as those cells keep dividing, they pick up different mutations 240 00:11:58,073 --> 00:12:02,673 along the way, so a tumor is usually a mixture of slightly different 241 00:12:02,673 --> 00:12:07,133 versions, and that mixture is exactly why treatments can be so stubborn. 242 00:12:07,603 --> 00:12:12,959 Matt: Ah, so the, a therapy then, I guess, clears out most of the cells- And the 243 00:12:12,959 --> 00:12:18,559 few that happen to be different seem to survive and grow, and that variety, I 244 00:12:18,559 --> 00:12:20,279 guess, is what makes it so hard to beat. 245 00:12:20,419 --> 00:12:21,339 Jen: Yeah, it is. 246 00:12:21,669 --> 00:12:26,169 And by the time a cell has gathered enough drivers, it's picked up a whole set of 247 00:12:26,169 --> 00:12:29,169 abilities a normal cell would never have. 248 00:12:29,799 --> 00:12:32,279 Chris: Yeah, and the classic list of, of those things is sometimes 249 00:12:32,279 --> 00:12:33,979 called the, the hallmarks of cancer. 250 00:12:33,979 --> 00:12:39,429 So it grows with no signal, it ignores every stop signal, and it 251 00:12:39,429 --> 00:12:43,729 refuses to undergo apoptosis or cell death, so it keeps accumulating. 252 00:12:43,849 --> 00:12:44,149 Jen: Mm. 253 00:12:44,539 --> 00:12:45,789 Matt: So it's broken then. 254 00:12:45,909 --> 00:12:48,349 Uh, it's broken all three of the rules we started with. 255 00:12:48,369 --> 00:12:52,269 It grows uninvited, it won't stop, and it won't step aside. 256 00:12:52,579 --> 00:12:54,639 Jen: All three, and then it adds more. 257 00:12:54,829 --> 00:12:56,819 It, it becomes effectively immortal. 258 00:12:56,849 --> 00:13:02,909 So normal chromosomes have protective caps on them called telomeres that shorten with 259 00:13:02,909 --> 00:13:05,489 each cell division until the cell retires. 260 00:13:05,779 --> 00:13:11,189 But cancer cells switch repair enzyme telomerase back on to rebuild them. 261 00:13:11,769 --> 00:13:15,779 Matt: So the cell reactivates an enzyme that resets its own 262 00:13:15,779 --> 00:13:18,609 counter and cancels its retirement? 263 00:13:18,649 --> 00:13:19,189 Jen: Mm. 264 00:13:20,099 --> 00:13:23,859 Matt: Sounds all a bit futuristic, a bit AI, a bit alien invasion- 265 00:13:24,069 --> 00:13:24,609 Jen: Yeah 266 00:13:24,789 --> 00:13:25,509 … Matt: if I'm honest. 267 00:13:25,539 --> 00:13:28,459 Chris: Yeah, and it's a genuinely strange trick. 268 00:13:28,619 --> 00:13:31,739 And there's one more that I'd say is arguably even more sneaky, 269 00:13:32,049 --> 00:13:36,019 because your immune system, which is obviously amazing, it's constantly 270 00:13:36,039 --> 00:13:38,139 patrolling for abnormal cells. 271 00:13:38,479 --> 00:13:42,469 And so c- a cancer that survives has learned to hide, basically. 272 00:13:42,879 --> 00:13:47,059 So it stops showing the surface flags that mark it as faulty, and 273 00:13:47,059 --> 00:13:48,469 it puts out checkpoint signals. 274 00:13:48,589 --> 00:13:53,129 So we're talking about molecules like, uh, PD-L1, which is a, a protein that 275 00:13:53,139 --> 00:13:54,999 tells immune cells to stand down. 276 00:13:55,779 --> 00:13:59,439 Jen: And there was a study in the Nature journal in 2025, and that 277 00:13:59,439 --> 00:14:01,399 found that it can go further still. 278 00:14:01,679 --> 00:14:05,819 So the cancer cell physically passes its own faulty mitochondria, 279 00:14:06,069 --> 00:14:10,389 the parts that generate a cell's energy, into the immune cells sent 280 00:14:10,399 --> 00:14:15,469 to destroy it, jamming their power supply so that they can't fight back. 281 00:14:15,889 --> 00:14:19,709 Matt: So it doesn't just hide from the immune system, it disables then 282 00:14:19,709 --> 00:14:21,839 the very cells sent to kill it. 283 00:14:22,369 --> 00:14:26,829 Every one of those, uh, is another rule it's learned to break then. 284 00:14:27,169 --> 00:14:29,719 Chris: That's it, and, and that's probably the natural place to end that mechanism. 285 00:14:29,729 --> 00:14:33,399 So with all these safeguards, the question is, you know, why does 286 00:14:33,399 --> 00:14:35,019 the cell not just stop itself? 287 00:14:35,449 --> 00:14:38,729 Um, and the important point here, when you go back to those millions 288 00:14:38,729 --> 00:14:42,069 and trillions that we talked about, is it almost always does. 289 00:14:42,139 --> 00:14:43,939 Matt: Mm. Yeah, and that's the bit to focus on, isn't it? 290 00:14:43,939 --> 00:14:48,339 Because after all, um, the, all what we've talked about is incredibly 291 00:14:48,339 --> 00:14:51,779 easy to feel like the odds are stacked against you and terrible. 292 00:14:52,129 --> 00:14:52,689 Jen: Yeah. 293 00:14:52,729 --> 00:14:56,849 They really aren't, though, and that's what we'd want people to take away. 294 00:14:57,119 --> 00:15:02,539 Given the sheer number of cell divisions every day, cancer is genuinely rare. 295 00:15:02,759 --> 00:15:07,689 So the safeguards catch the overwhelming majority, and it's only the very unlucky 296 00:15:07,699 --> 00:15:12,189 pile-up of failures in the same cell over a long time that gets through. 297 00:15:12,931 --> 00:15:16,221 Chris: Yeah, and importantly, every one of the steps we've named is now 298 00:15:16,221 --> 00:15:17,851 something that research c- can target. 299 00:15:17,861 --> 00:15:17,871 Mm. 300 00:15:17,881 --> 00:15:18,241 Jen: And 301 00:15:18,541 --> 00:15:22,611 Chris: that's from, uh, drugs that block oncogenes to ones that switch 302 00:15:22,911 --> 00:15:24,391 the immune system response back on. 303 00:15:24,851 --> 00:15:29,591 And so understanding how the cell breaks each rule is what tells us how to step in. 304 00:15:29,591 --> 00:15:33,281 And, and let's be honest, the advances are still incredible 305 00:15:33,281 --> 00:15:34,431 if you think where we are today- 306 00:15:34,501 --> 00:15:34,761 Matt: Yeah. 307 00:15:34,781 --> 00:15:36,011 Chris: Yeah … versus even 10 years ago. 308 00:15:36,051 --> 00:15:37,201 Jen: Absolutely incredible. 309 00:15:37,201 --> 00:15:37,301 Absolutely, yeah. 310 00:15:37,301 --> 00:15:37,591 Yeah. 311 00:15:37,631 --> 00:15:38,431 Matt: Yeah, they really are. 312 00:15:38,771 --> 00:15:41,221 Okay, so let's bring this home. 313 00:15:41,431 --> 00:15:44,201 Our original question: Why do cells turn cancerous? 314 00:15:44,701 --> 00:15:48,651 Jen: Because a single cell accumulates driver mutations 315 00:15:48,651 --> 00:15:50,991 that break the rules it lives by. 316 00:15:51,221 --> 00:15:56,911 So the proto-oncogenes that say grow get locked on, the tumor suppressors 317 00:15:56,941 --> 00:16:02,191 that say stop, repair, or self-destruct get switched off, and the safeguards 318 00:16:02,191 --> 00:16:04,741 that will catch all of that fail too. 319 00:16:04,951 --> 00:16:08,951 So you stack up enough, usually over years, and the cell stops 320 00:16:08,951 --> 00:16:13,991 being cooperative, um, with the body and starts acting for itself. 321 00:16:14,401 --> 00:16:14,641 Chris: Yeah. 322 00:16:14,681 --> 00:16:18,391 A- and as we said before, the thing to keep firmly in mind here is that 323 00:16:18,391 --> 00:16:22,061 it's rare- Mm … precisely because the body is so good at catching it. 324 00:16:22,421 --> 00:16:25,591 So what we're describing is the exception that slips through an 325 00:16:25,591 --> 00:16:28,051 extraordinary amount of protection. 326 00:16:28,181 --> 00:16:28,471 Jen: Mm. 327 00:16:28,561 --> 00:16:33,351 Matt: And weirdly, I find that reassuring rather than frightening, which is 328 00:16:33,371 --> 00:16:36,031 perhaps not how I felt at the start of the conversation about cancer. 329 00:16:36,171 --> 00:16:36,561 Jen: Yeah. 330 00:16:36,561 --> 00:16:40,001 It's definitely helpful to understand the process in this case. 331 00:16:40,641 --> 00:16:43,981 So that's why cells turn cancerous. 332 00:16:44,081 --> 00:16:45,711 That is it for this week. 333 00:16:46,031 --> 00:16:49,711 Make sure you hit that subscribe button and tell us in the comments what 334 00:16:49,711 --> 00:16:51,621 questions you'd like us to explore. 335 00:16:52,111 --> 00:16:53,651 Thanks for geeking out with us. 336 00:16:53,831 --> 00:16:55,571 But for now, that's it from me. 337 00:16:56,011 --> 00:16:56,861 Matt: That's it from me. 338 00:16:57,221 --> 00:16:57,721 Chris: And that's it from 339 00:16:57,721 --> 00:16:58,081 me. 340 00:16:58,281 --> 00:16:58,971 Jen: Bye for now