WEBVTT 00:00:00.000 --> 00:00:01.620 You know, uh, I was looking through the stack 00:00:01.620 --> 00:00:03.759 of papers for today's deep dive and I honestly 00:00:03.759 --> 00:00:07.259 didn't know whether to classify this one as a 00:00:07.259 --> 00:00:10.880 biology discussion or, or a philosophy one. A 00:00:10.880 --> 00:00:12.519 philosophy one. That's a pretty heavy way to 00:00:12.519 --> 00:00:15.080 start. It is, yeah. But bear with me here. Because 00:00:15.080 --> 00:00:17.460 usually we tend to think of our body cells as 00:00:17.460 --> 00:00:20.699 these, you know, finished products. Like, a heart 00:00:20.699 --> 00:00:22.460 cell is a heart cell. Right. A brain cell is 00:00:22.460 --> 00:00:24.059 a brain cell. They just sit there and do their 00:00:24.059 --> 00:00:26.300 job. But the sources we're pulling from today, 00:00:26.440 --> 00:00:28.719 these scientific literature summaries and genetic 00:00:28.719 --> 00:00:32.539 databases, they suggest something way more chaotic 00:00:32.539 --> 00:00:35.539 about our biology. They suggest our cells are 00:00:35.539 --> 00:00:37.780 constantly fighting to remember who they are. 00:00:38.009 --> 00:00:40.149 That is actually a brilliant way to frame it. 00:00:40.390 --> 00:00:43.149 Right. And if they forget, even for a day, the 00:00:43.149 --> 00:00:45.409 whole system just collapses. Exactly. Because 00:00:45.409 --> 00:00:47.649 we usually look at biology as architecture, you 00:00:47.649 --> 00:00:51.289 know, building a structure. But this story is 00:00:51.289 --> 00:00:53.929 really about maintenance. It's about the active, 00:00:54.009 --> 00:00:56.950 constant effort required just to stay functional. 00:00:57.450 --> 00:00:59.509 And the main character in this story, the thing 00:00:59.509 --> 00:01:01.990 doing that maintenance, is a specific protein. 00:01:02.250 --> 00:01:05.609 It's called Myelin Regulatory Factor. Or MYRF 00:01:05.609 --> 00:01:08.900 for short. Right. MYRF. And our mission today 00:01:08.900 --> 00:01:11.879 for you, the listener, is to unpack this protein, 00:01:12.200 --> 00:01:14.500 because it has everything. It's got this violent 00:01:14.500 --> 00:01:16.540 mechanism where it literally has to mutilate 00:01:16.540 --> 00:01:18.439 itself to work. Yeah, the self -chopping part. 00:01:18.599 --> 00:01:21.340 It's wild. Plus, it has direct ties to severe 00:01:21.340 --> 00:01:24.200 human diseases like multiple sclerosis. And this 00:01:24.200 --> 00:01:26.840 is my personal favorite part. It has a family 00:01:26.840 --> 00:01:29.180 tree that connects the hard wiring of our complex 00:01:29.180 --> 00:01:32.239 human brains to a single, swirled slime mold 00:01:32.239 --> 00:01:34.269 living in the dirt. The slime mold connection 00:01:34.269 --> 00:01:35.870 is definitely my favorite part too. It really 00:01:35.870 --> 00:01:38.250 puts human arrogance in check, doesn't it? It 00:01:38.250 --> 00:01:40.730 really does. So let's just get into it. What 00:01:40.730 --> 00:01:43.530 exactly is MyRF? Let's start with the basics, 00:01:43.750 --> 00:01:45.829 but maybe go a bit deeper than the usual high 00:01:45.829 --> 00:01:48.719 school bio class. Sure. So we know genes are 00:01:48.719 --> 00:01:50.980 the instruction manual for the body. Right, the 00:01:50.980 --> 00:01:53.859 blueprints. Exactly. But instructions are useless 00:01:53.859 --> 00:01:56.359 without a foreman to actually shout orders and 00:01:56.359 --> 00:01:59.180 organize the crew. In biology, that foreman is 00:01:59.180 --> 00:02:01.060 a transcription factor. Okay, so transcription 00:02:01.060 --> 00:02:03.439 factors bind to the DNA and basically tell the 00:02:03.439 --> 00:02:06.719 cell, read this page, ignore that page. You got 00:02:06.719 --> 00:02:09.860 it. But MYRF isn't just some middle -manager 00:02:09.860 --> 00:02:12.979 transcription factor. It is a master regulator. 00:02:13.580 --> 00:02:16.319 In the context of the brain, specifically the 00:02:16.319 --> 00:02:19.919 central nervous system, MYRF is the absolute 00:02:19.919 --> 00:02:22.960 boss for producing myelin. And myelin being the 00:02:22.960 --> 00:02:25.659 physical insulation on our nerves. Correct. It's 00:02:25.659 --> 00:02:28.139 this fatty sheath that wraps around the axons 00:02:28.139 --> 00:02:30.360 of our nerve cells, and it is absolutely critical 00:02:30.360 --> 00:02:33.099 for speed. Like coating on a copper wire. Exactly 00:02:33.099 --> 00:02:35.039 like that. If you don't have myelin, electrical 00:02:35.039 --> 00:02:37.699 signals in your brain just crawl. If you do have 00:02:37.699 --> 00:02:40.000 it, they zoom. Makes sense. But to make that 00:02:40.000 --> 00:02:42.740 myelin, the cell needs to pump out a very specific 00:02:42.740 --> 00:02:45.879 recipe of proteins. If you look at the literature, 00:02:45.879 --> 00:02:48.659 you'll see this alphabet soup of acronyms. Yeah, 00:02:48.680 --> 00:02:52.159 I saw those PLP1, MBP. MAG, Melody, yeah. It's 00:02:52.159 --> 00:02:54.639 a lot of letters. It is. But just think of PLP1 00:02:54.639 --> 00:02:57.639 and MBP as the bricks and mortar of the myelin 00:02:57.639 --> 00:03:00.180 wall. Now, the research shows that the genes 00:03:00.180 --> 00:03:02.759 for those materials are completely silent on 00:03:02.759 --> 00:03:04.479 their own. They don't do anything by themselves. 00:03:04.599 --> 00:03:06.319 Nothing at all. You can have all the raw material. 00:03:06.280 --> 00:03:08.879 sitting right there, but without MYRF to sign 00:03:08.879 --> 00:03:11.919 the work order, nothing gets built. So MYRF is 00:03:11.919 --> 00:03:14.419 the one turning the key. If it's absent, the 00:03:14.419 --> 00:03:16.719 factory is totally dark. Precisely. And this 00:03:16.719 --> 00:03:18.740 mechanism is highly specific. You don't just 00:03:18.740 --> 00:03:21.360 find MYRF floating around everywhere in the body. 00:03:21.879 --> 00:03:25.060 In the brain, it is strictly found in mature 00:03:25.060 --> 00:03:28.259 myelinating oligodendrocytes. Oligodendrocytes 00:03:28.259 --> 00:03:30.419 being the specific cells that actually wrap the 00:03:30.419 --> 00:03:32.900 nerves. Right. Although I did catch a really 00:03:32.900 --> 00:03:34.860 weird detail in the gene expression data from 00:03:34.860 --> 00:03:38.599 the sources. It said MYRF also pops up in the 00:03:38.599 --> 00:03:41.120 stomach. Oh, you caught that. Yeah, specifically 00:03:41.120 --> 00:03:44.620 the pyloric antrum, which seems like a huge jump 00:03:44.620 --> 00:03:48.039 from the brain. You have a sharp eye. Yes, biology 00:03:48.039 --> 00:03:50.819 is rarely tidy. Evolution loves to reuse its 00:03:50.819 --> 00:03:54.560 tools. So MYRF is also expressed in the stomach 00:03:54.560 --> 00:03:56.860 and parts of the intestine. What's it doing down 00:03:56.860 --> 00:03:59.080 there? It's likely helping mucous cells differentiate. 00:03:59.210 --> 00:04:01.330 But the stakes are very different. I mean, if 00:04:01.330 --> 00:04:03.250 MYRF glitches in the stomach, you might have 00:04:03.250 --> 00:04:05.590 some digestion issues. Right. But if it glitches 00:04:05.590 --> 00:04:08.050 in the brain, you lose the ability to move or 00:04:08.050 --> 00:04:11.090 think clearly. So for our purposes today, the 00:04:11.090 --> 00:04:13.389 central nervous system is the main stage. OK, 00:04:13.430 --> 00:04:16.389 that makes sense. So we have this foreman, MYRF. 00:04:16.610 --> 00:04:18.629 He's in charge of the myelin crew in the brain. 00:04:19.490 --> 00:04:21.269 But this is where the story gets really weird 00:04:21.269 --> 00:04:24.959 for me. The mechanism. Yeah. Because in most 00:04:24.959 --> 00:04:27.560 textbooks, a transcription factor is made in 00:04:27.560 --> 00:04:29.980 the cytoplasm, and then it just walks into the 00:04:29.980 --> 00:04:32.079 nucleus, right? It's a simple commute. Normally, 00:04:32.319 --> 00:04:34.959 yes. But the structural biology papers here describe 00:04:34.959 --> 00:04:37.680 something way more complicated for MYRF. This 00:04:37.680 --> 00:04:41.910 was a massive aha moment for biochemists. MyRF 00:04:41.910 --> 00:04:45.009 is what we call a membrane -associated transcription 00:04:45.009 --> 00:04:47.529 factor. Okay, break that down for us. When it's 00:04:47.529 --> 00:04:50.029 first synthesized by the cell, it isn't free 00:04:50.029 --> 00:04:52.490 to float around. It is physically anchored to 00:04:52.490 --> 00:04:55.350 the membrane of the endoplasmic reticulum. ER. 00:04:55.610 --> 00:04:57.550 That's like the cell's factory floor. Right. 00:04:57.610 --> 00:05:00.509 So imagine your job is to go into the CEO's office, 00:05:00.610 --> 00:05:03.189 the nucleus, and sign some crucial papers. Okay. 00:05:03.250 --> 00:05:05.889 But you are handcuffed to a radiator in the basement. 00:05:06.009 --> 00:05:08.930 You physically cannot get to the DNA. That seems 00:05:08.930 --> 00:05:11.899 incredibly inefficient. Why would evolution design 00:05:11.899 --> 00:05:14.420 a system where the key player is trapped outside 00:05:14.420 --> 00:05:16.899 the very room where it needs to work? Well, it's 00:05:16.899 --> 00:05:19.860 all about control. We have to understand that 00:05:19.860 --> 00:05:22.279 myelination is a massive commitment for a cell. 00:05:22.759 --> 00:05:26.300 How so? For a cell to become an oligodendrocyte 00:05:26.300 --> 00:05:29.439 and wrap an axon, it has to change its entire 00:05:29.439 --> 00:05:32.519 shape. It produces huge amounts of lipid membrane. 00:05:32.879 --> 00:05:35.319 It's an irreversible transformation. Oh, I see. 00:05:35.379 --> 00:05:37.459 You do not want that happening by accident. Exactly. 00:05:37.660 --> 00:05:40.220 The handcuffs are a safety feature. It prevents 00:05:40.220 --> 00:05:42.980 the protein from bumping into the DNA and accidentally 00:05:42.980 --> 00:05:45.240 starting a massive construction project that 00:05:45.240 --> 00:05:47.259 the cell just isn't ready for. So it builds up 00:05:47.259 --> 00:05:49.699 this reservoir of tethered proteins just waiting 00:05:49.699 --> 00:05:51.800 in the basement for the signal. Exactly. But 00:05:51.800 --> 00:05:54.420 to get the job done, eventually those handcuffs 00:05:54.420 --> 00:05:58.620 have to come off. And the notes say MYRF undergoes 00:05:58.620 --> 00:06:02.060 autoproteolytic cleavage. Which is just a Fancy 00:06:02.060 --> 00:06:04.540 scientific term for saying it cuts itself. That's 00:06:04.540 --> 00:06:06.220 pretty metal. It literally chops its own head 00:06:06.220 --> 00:06:09.040 off. Effectively, yes. The protein folds into 00:06:09.040 --> 00:06:11.660 a very specific shape, and that shape creates 00:06:11.660 --> 00:06:13.959 molecular scissors within its own structure. 00:06:14.000 --> 00:06:16.839 Wow. So when the right signal comes, it snaps 00:06:16.839 --> 00:06:19.199 the peptide bond, holding it to that membrane 00:06:19.199 --> 00:06:22.500 anchor. And that releases it. Yes. It releases 00:06:22.500 --> 00:06:25.600 what we call the N -terminal domain, the active 00:06:25.600 --> 00:06:28.139 part of the protein, which then rushes straight 00:06:28.139 --> 00:06:30.920 into the nucleus. And I'm guessing... Unlike 00:06:30.920 --> 00:06:32.680 a pair of metal handcuffs that you could just 00:06:32.680 --> 00:06:34.920 unlock and lock again. Yeah, you can't uncut 00:06:34.920 --> 00:06:37.779 a protein No, you cannot and that's the absolute 00:06:37.779 --> 00:06:40.639 key point here. It is a permanent clean break 00:06:40.639 --> 00:06:43.740 once that cleavage happens There is no going 00:06:43.740 --> 00:06:46.500 back. The cell has crossed the Rubicon. It has. 00:06:46.579 --> 00:06:49.319 It is fully committed to becoming a myelin -producing 00:06:49.319 --> 00:06:52.319 cell. It creates this huge surge, a flood of 00:06:52.319 --> 00:06:55.379 activation, that turns on all those genes PLP1, 00:06:55.459 --> 00:06:57.939 MVP, at the exact same time. It coordinates the 00:06:57.939 --> 00:07:00.060 entire transformation. That's brilliant. It really 00:07:00.060 --> 00:07:02.160 is an elegant system. Okay, so that explains 00:07:02.160 --> 00:07:04.180 how we build the insulation in the first place. 00:07:04.420 --> 00:07:07.040 We grow up, our cells trigger the suicide switch 00:07:07.040 --> 00:07:09.779 in the protein, the myelin gets built, and we 00:07:09.779 --> 00:07:11.899 learn to walk and talk. Right. But I want to 00:07:11.899 --> 00:07:14.399 pivot to to what happens after. Because I think 00:07:14.399 --> 00:07:17.300 you and I, and probably everyone listening, assume 00:07:17.300 --> 00:07:19.420 that once your nerves are insulated, you're good 00:07:19.420 --> 00:07:22.019 to go. The house is built. The contractor goes 00:07:22.019 --> 00:07:25.180 home. Exactly. But there was this landmark study 00:07:25.180 --> 00:07:27.959 mentioned in the sources involving mice that 00:07:27.959 --> 00:07:30.360 completely shattered that idea. Oh, the adult 00:07:30.360 --> 00:07:33.759 ablation study. Yes. Walk us through that, because 00:07:33.759 --> 00:07:37.500 this blew my mind. So scientists bred these genetically 00:07:37.500 --> 00:07:40.199 modified mice. They let them grow up entirely 00:07:40.199 --> 00:07:42.639 normally. They built all their myelin, became 00:07:42.639 --> 00:07:47.300 healthy, fully functional adult mice. Then the 00:07:47.300 --> 00:07:50.199 researchers flipped a genetic switch that specifically 00:07:50.199 --> 00:07:54.000 deleted the MYRF gene in these adult mice. So 00:07:54.000 --> 00:07:55.779 they fired the contractor after the house was 00:07:55.779 --> 00:07:59.199 already finished. Exactly. If the static structure 00:07:59.199 --> 00:08:01.620 theory was true, if myelin was just like plastic 00:08:01.620 --> 00:08:03.639 coating on a wire, deleting the gene for the 00:08:03.639 --> 00:08:05.319 builder shouldn't matter at all, the wire is 00:08:05.319 --> 00:08:07.079 already coated. Right. The myelin is already 00:08:07.079 --> 00:08:09.220 there. But that's not what happened. Not even 00:08:09.220 --> 00:08:11.519 close. The results were catastrophic. The sources 00:08:11.519 --> 00:08:14.779 say the expression of the myelin genes just plummeted. 00:08:14.839 --> 00:08:17.220 Dropped off a cliff. Yeah. And physically, the 00:08:17.220 --> 00:08:19.040 mice started to lose the myelin they already 00:08:19.040 --> 00:08:22.100 had. The insulation began to unravel and degrade. 00:08:22.259 --> 00:08:25.410 Just fall apart? Yeah. The mice develop severe 00:08:25.410 --> 00:08:27.870 tremors, ataxia, which is a loss of coordination, 00:08:28.129 --> 00:08:30.810 and eventually paralysis. That is terrifying. 00:08:31.589 --> 00:08:33.389 Because it means the insulation on our nerves 00:08:33.389 --> 00:08:36.289 isn't a one -time construction project. It's 00:08:36.289 --> 00:08:38.950 what? Like a subscription service. That is a 00:08:38.950 --> 00:08:41.529 perfect analogy. Yes, it's a subscription service. 00:08:41.649 --> 00:08:44.549 Wow. The oligodendrocyte has to constantly renew 00:08:44.549 --> 00:08:47.549 its subscription to being a myelin cell. It literally 00:08:47.549 --> 00:08:51.110 has to wake up every single day, process MYRF, 00:08:51.409 --> 00:08:53.970 cut the tether, and send the signal to the nucleus 00:08:53.970 --> 00:08:56.049 just to maintain the status quo. Yeah, and if 00:08:56.049 --> 00:08:58.350 the subscription lapses. The service gets cut 00:08:58.350 --> 00:09:01.470 off, the cell forgets its identity, it stops 00:09:01.470 --> 00:09:03.710 producing the proteins needed to maintain the 00:09:03.710 --> 00:09:06.009 sheath, and the whole nervous system starts to 00:09:06.009 --> 00:09:08.669 fail. This brings us right back to that idea 00:09:08.669 --> 00:09:10.970 of fragility we talked about at the start. We 00:09:10.970 --> 00:09:13.750 aren't these permanent statues. We are constant, 00:09:13.929 --> 00:09:16.149 active processes. Which is why maintenance is 00:09:16.149 --> 00:09:18.350 so critical. And this connects directly to human 00:09:18.350 --> 00:09:20.230 pathology, doesn't it, when the switch fails? 00:09:20.309 --> 00:09:23.210 It does. The most obvious parallel is multiple 00:09:23.210 --> 00:09:26.590 sclerosis, or MS. Now, typically, we think of 00:09:26.590 --> 00:09:29.809 MS as an autoimmune disease. The immune system 00:09:29.809 --> 00:09:32.509 actively attacks the myelin. That's what I've 00:09:32.509 --> 00:09:36.039 always heard. But the end result in these MyRF 00:09:36.039 --> 00:09:39.720 deleted mice looks almost identical to end -stage 00:09:39.720 --> 00:09:42.899 MS in humans. It shows that you can arrive at 00:09:42.899 --> 00:09:46.200 severe demyelination from two completely different 00:09:46.200 --> 00:09:49.059 directions. An external attack or an internal 00:09:49.059 --> 00:09:51.440 failure of maintenance. Exactly. There was another 00:09:51.440 --> 00:09:53.360 disease in the research that I had never connected 00:09:53.360 --> 00:09:57.500 to this before. Neiman -Pick type C1. Oh, yes. 00:09:57.600 --> 00:09:59.639 I've heard of it, but I always thought of it 00:09:59.639 --> 00:10:02.009 as a metabolic thing. a cholesterol problem. 00:10:02.090 --> 00:10:04.490 It is a cholesterol storage disorder. Yeah. And 00:10:04.490 --> 00:10:06.350 it's a really heartbreaking condition, often 00:10:06.350 --> 00:10:09.190 affecting children. But neurologically, it presents 00:10:09.190 --> 00:10:11.889 as dysmyelination, basically bad insulation. 00:10:12.129 --> 00:10:13.809 For a long time, the dots weren't connected, 00:10:13.990 --> 00:10:15.490 right? Yeah. Why would a cholesterol problem 00:10:15.490 --> 00:10:17.190 stop the brain from being insulated? Right. It 00:10:17.190 --> 00:10:19.610 was a mystery. But MYRS is the missing link here. 00:10:19.789 --> 00:10:22.210 The hypothesis connecting them is incredibly 00:10:22.210 --> 00:10:24.830 elegant. Think back to where MYRF lives before 00:10:24.830 --> 00:10:27.429 it cuts itself. The ER membrane, handcuffed to 00:10:27.429 --> 00:10:30.019 the radiator. And what are cellular membranes 00:10:30.019 --> 00:10:33.779 mostly made of? Lipids. Cholesterol. Exactly. 00:10:34.340 --> 00:10:37.899 In Neiman Pick type C1, the cell can't transport 00:10:37.899 --> 00:10:40.279 cholesterol correctly, so the composition of 00:10:40.279 --> 00:10:42.240 that membrane gets totally messed up. It becomes 00:10:42.240 --> 00:10:45.299 too rigid or jammed. Wait, so the molecular scissors 00:10:45.299 --> 00:10:48.360 get stuck. That's the current thinking. The membrane 00:10:48.360 --> 00:10:51.940 environment is wrong, so the MYRF protein can't 00:10:51.940 --> 00:10:54.519 fold correctly to perform that self -cutting 00:10:54.519 --> 00:10:56.940 trick. So the MYRF is there. The gene is perfectly 00:10:56.940 --> 00:10:58.820 fine, but the protein is just trapped in the 00:10:58.820 --> 00:11:01.299 basement. Yep. It can't get to the nucleus to 00:11:01.299 --> 00:11:04.970 do its job. That is wild. So you have this metabolic 00:11:04.970 --> 00:11:08.289 disease that masquerades as a genetic failure, 00:11:08.450 --> 00:11:11.370 all because the physical mechanics of the cell 00:11:11.370 --> 00:11:13.490 are just gummed up. It illustrates perfectly 00:11:13.490 --> 00:11:15.809 how interconnected everything is in biology. 00:11:16.129 --> 00:11:18.230 You change the cholesterol level, you trap the 00:11:18.230 --> 00:11:20.809 transcription factor, you lose the myelin, you 00:11:20.809 --> 00:11:23.470 lose brain function. It's a domino effect. It 00:11:23.470 --> 00:11:26.049 really emphasizes that MYRF is a bottleneck. 00:11:26.190 --> 00:11:27.850 It's a single point of failure for the whole 00:11:27.850 --> 00:11:30.269 system. True. But a single point of failure also 00:11:30.269 --> 00:11:32.509 means it's a single point of opportunity. You're 00:11:32.509 --> 00:11:34.529 talking about the spinal cord injury research 00:11:34.529 --> 00:11:36.710 from the sources. Yes. This is the flip side 00:11:36.710 --> 00:11:39.070 of the coin. We know that when the spinal cord 00:11:39.070 --> 00:11:41.809 is injured, the body actually does try to repair 00:11:41.809 --> 00:11:44.029 it. Really? I thought spinal nerves couldn't 00:11:44.029 --> 00:11:47.809 heal. They struggle to, but the body tries. It 00:11:47.809 --> 00:11:51.169 recruits these cells called oligodendrocyte precursor 00:11:51.169 --> 00:11:54.590 cells, or OPCs, to the site of the injury. Like 00:11:54.590 --> 00:11:56.789 baby cells waiting to grow up and become myelin 00:11:56.789 --> 00:12:00.990 wrappers. Exactly. And the data shows MYRF activity 00:12:00.990 --> 00:12:03.389 actually spikes during this time. It surges. 00:12:03.470 --> 00:12:06.490 It surges. It's the body attempting to initiate 00:12:06.490 --> 00:12:08.809 that burn -the -ships commitment to repair the 00:12:08.809 --> 00:12:11.169 insulation. But here's the kicker from the studies. 00:12:11.169 --> 00:12:14.379 Okay. If researchers artificially repress MYRF 00:12:14.379 --> 00:12:17.019 in those precursor cells, the functional recovery 00:12:17.019 --> 00:12:20.000 is significantly delayed. The repair fails. So 00:12:20.000 --> 00:12:22.299 the baby cells show up to the injury, they hang 00:12:22.299 --> 00:12:24.600 around, but they don't actually wrap the nerves. 00:12:24.700 --> 00:12:26.700 They can't commit. They can't commit without 00:12:26.700 --> 00:12:29.480 MYRF. It's the right limiting step for healing. 00:12:29.580 --> 00:12:32.320 Which naturally leads to the big what if. Exactly. 00:12:32.480 --> 00:12:34.919 What if we could develop a drug that artificially 00:12:34.919 --> 00:12:38.480 stimulates MYRF? If we could force those precursor 00:12:38.480 --> 00:12:41.620 cells... to cut the tether and flood the nucleus 00:12:41.620 --> 00:12:43.899 with the active protein. We could potentially 00:12:43.899 --> 00:12:46.559 kickstart remyelination in spinal injuries or 00:12:46.559 --> 00:12:48.679 in diseases like MS where the repair process 00:12:48.679 --> 00:12:50.460 has stalled out. Instead of just trying to stop 00:12:50.460 --> 00:12:52.620 the immune system from doing more damage, we 00:12:52.620 --> 00:12:54.779 could actively drive the reconstruction of the 00:12:54.779 --> 00:12:57.700 brain. That is the hope. It's an incredibly exciting 00:12:57.700 --> 00:13:00.379 area of research. It is a really hopeful prospect. 00:13:00.879 --> 00:13:03.340 But before we wrap up, I want to zoom out. Way 00:13:03.340 --> 00:13:06.269 out. because we teased the slime mold at the 00:13:06.269 --> 00:13:08.289 very beginning of the deep dive, and I do not 00:13:08.289 --> 00:13:10.049 want to leave the listener hanging. We absolutely 00:13:10.049 --> 00:13:13.470 cannot forget the slime mold. So, looking at 00:13:13.470 --> 00:13:16.509 the orthologs section of the genetic database 00:13:16.509 --> 00:13:19.809 data. Orthologs being genes in different species 00:13:19.809 --> 00:13:22.590 that evolved from a common ancestor. Right. So 00:13:22.590 --> 00:13:25.919 humans have the MYRF gene on chromosome 11. Mice 00:13:25.919 --> 00:13:28.259 have their version, spelled with lowercase letters, 00:13:28.779 --> 00:13:31.620 on chromosome 19. Typical mammalian stuff. But 00:13:31.620 --> 00:13:33.799 the list goes on. There's a nematode worm, C. 00:13:33.820 --> 00:13:37.779 elegans, with a gene called PQN47. And then there's 00:13:37.779 --> 00:13:40.139 the slime mold, Dictyostelium, with a gene called 00:13:40.139 --> 00:13:43.879 MyRFa. And just to be extremely clear for everyone 00:13:43.879 --> 00:13:47.419 listening, slime molds do not have brains. No. 00:13:47.659 --> 00:13:49.639 They don't have nerves. They definitely don't 00:13:49.639 --> 00:13:52.019 have myelin. They are single -celled amoebas 00:13:52.019 --> 00:13:54.259 that live in the dirt. So why on earth do they 00:13:54.259 --> 00:13:57.399 have a myelin regulatory factor? Or at least... 00:13:57.019 --> 00:13:59.600 the ancient grandfather of one. This is such 00:13:59.600 --> 00:14:02.399 a beautiful example of how evolution works. Evolution 00:14:02.399 --> 00:14:05.379 doesn't reinvent the wheel. It repurposes it. 00:14:05.539 --> 00:14:07.480 OK, how so? Well, when researchers looked at 00:14:07.480 --> 00:14:10.480 the structure of the MyRF protein, specifically 00:14:10.480 --> 00:14:13.720 the part that binds to the DNA, they found it 00:14:13.720 --> 00:14:16.840 is incredibly similar to a protein found in yeast. 00:14:17.000 --> 00:14:20.840 Yeast? Yeah, a protein called NDT80. NDT80. And 00:14:20.840 --> 00:14:23.320 what does that do in yeast? In yeast, it regulates 00:14:23.320 --> 00:14:26.340 sporulation. When the yeast is starving or stressed, 00:14:26.350 --> 00:14:29.769 out, NDT80 triggers a massive structural change 00:14:29.769 --> 00:14:32.269 to turn the yeast cell into a spore so it can 00:14:32.269 --> 00:14:35.210 survive. So it's a survival switch. A very dramatic 00:14:35.210 --> 00:14:37.649 one. And in the slime mold Dictyostelium, it's 00:14:37.649 --> 00:14:39.929 even cooler. Hit me. When slime molds run out 00:14:39.929 --> 00:14:42.590 of food, they stop being individuals. They aggregate 00:14:42.590 --> 00:14:45.230 together to form this multicellular slug. I've 00:14:45.230 --> 00:14:47.169 seen time lapse videos of this. It's totally 00:14:47.169 --> 00:14:51.330 alien looking. It is. Then that slug stands up 00:14:51.330 --> 00:14:54.269 to form a fruiting body. Basically, a stalk with 00:14:54.269 --> 00:14:57.009 a ball of spores on top. But here's the dilemma 00:14:57.009 --> 00:15:00.330 for the slime mold. If you are a single cell 00:15:00.330 --> 00:15:03.409 inside that slug, you have to make a decision. 00:15:03.649 --> 00:15:05.750 What decision? Are you going to be a spore which 00:15:05.750 --> 00:15:08.850 gets to fly away and reproduce and live? Or are 00:15:08.850 --> 00:15:11.330 you going to be the stalk which holds the spores 00:15:11.330 --> 00:15:14.070 up? but dies in the process. Oh, wow. It's an 00:15:14.070 --> 00:15:16.850 altruistic sacrifice. It is. It's pre -stock 00:15:16.850 --> 00:15:19.230 differentiation. And the gene that drives that 00:15:19.230 --> 00:15:21.929 decision, the gene that says, I commit to becoming 00:15:21.929 --> 00:15:24.769 the structural stock and giving up my individuality, 00:15:25.149 --> 00:15:28.590 is the orthologa of MYRF. That is unbelievable. 00:15:28.669 --> 00:15:31.629 So the common thread across hundreds of millions 00:15:31.629 --> 00:15:34.769 of years isn't myelin at all. The common thread 00:15:34.769 --> 00:15:37.570 is irreversible structural commitment. Exactly. 00:15:37.850 --> 00:15:40.269 Evolution developed a mechanism, this membrane 00:15:40.269 --> 00:15:43.289 tethered cell protein to act as a definitive 00:15:43.289 --> 00:15:45.929 one -way switch. The master switch. Yes. In slime 00:15:45.929 --> 00:15:48.610 molds, the switch says, build a stock. In humans, 00:15:48.809 --> 00:15:51.419 the switch says, build a myelin sheath. The hardware 00:15:51.419 --> 00:15:53.620 changed, but the software logic is identical. 00:15:53.779 --> 00:15:56.159 It's a p53 -like transcription factor, right? 00:15:56.179 --> 00:15:58.240 That's what the notes called it. Yes. It shares 00:15:58.240 --> 00:16:01.700 structural similarities with p53, which scientists 00:16:01.700 --> 00:16:04.340 call the guardian of the genome. These are ancient 00:16:04.340 --> 00:16:07.519 high -stakes managers. They control the ultimate 00:16:07.519 --> 00:16:10.019 destiny of the cell. It really puts things in 00:16:10.019 --> 00:16:12.440 perspective for you. I mean, the machinery that 00:16:12.440 --> 00:16:15.059 allows my brain to process this conversation 00:16:15.059 --> 00:16:18.179 right now, to understand language and logic. 00:16:18.399 --> 00:16:21.529 Yeah. It's powered by a mechanism borrowed from 00:16:21.529 --> 00:16:24.309 a starving worm deciding to turn into a spore. 00:16:24.649 --> 00:16:27.750 We are walking mosaics of ancient biology. We 00:16:27.750 --> 00:16:30.230 really stand on the shoulders of giants and slime 00:16:30.230 --> 00:16:32.570 molds. That's a t -shirt right there. Yeah. So 00:16:32.570 --> 00:16:35.389 if we had to distill this entire deep dive into 00:16:35.389 --> 00:16:37.950 one key takeaway for someone listening to this 00:16:37.950 --> 00:16:41.289 on their commute, what is it? For me, it's the 00:16:41.289 --> 00:16:43.669 realization that our biological identity is an 00:16:43.669 --> 00:16:46.870 active, ongoing process. We aren't static. The 00:16:46.870 --> 00:16:48.830 subscription service? Exactly. The myelin in 00:16:48.830 --> 00:16:50.850 your brain is being maintained right now, this 00:16:50.850 --> 00:16:53.629 very second, by millions of little proteins cutting 00:16:53.629 --> 00:16:55.850 themselves free from membranes just to keep the 00:16:55.850 --> 00:16:58.110 lights on. And that system is incredibly fragile. 00:16:58.299 --> 00:17:02.120 It is fragile. It can be disrupted by genetic 00:17:02.120 --> 00:17:05.539 mutations, by metabolic changes like cholesterol 00:17:05.539 --> 00:17:08.660 in name and pick, or by a physical injury. Right. 00:17:08.980 --> 00:17:11.160 But understanding that fragility is the very 00:17:11.160 --> 00:17:13.799 first step to fixing it. If we know the switch 00:17:13.799 --> 00:17:17.099 exists, we can learn how to flip it. We know 00:17:17.099 --> 00:17:19.589 the mechanism. Now we just need to master the 00:17:19.589 --> 00:17:22.130 controls. That's the future of regenerative medicine 00:17:22.130 --> 00:17:24.410 right there, moving from just treating symptoms 00:17:24.410 --> 00:17:26.970 to actually rebuilding the architecture of the 00:17:26.970 --> 00:17:29.529 brain. Well, I am never going to look at a slime 00:17:29.529 --> 00:17:31.750 mold or my own nervous system, for that matter, 00:17:31.890 --> 00:17:34.190 the same way again. It's amazing what you find 00:17:34.190 --> 00:17:36.369 when you dig into the footnotes of a genetic 00:17:36.369 --> 00:17:39.150 database. The devil and the delight is always 00:17:39.150 --> 00:17:41.529 in the details. Thanks for diving in with us 00:17:41.529 --> 00:17:44.319 today. Keep those neurons firing and give your 00:17:44.319 --> 00:17:47.119 MYRF proteins a mental high five for keeping 00:17:47.119 --> 00:17:49.640 the insulation intact. We'll see you on the next 00:17:49.640 --> 00:17:51.339 deep dive. Stay curious everyone!