WEBVTT 00:00:00.000 --> 00:00:04.059 What if I told you that the energy your brain 00:00:04.059 --> 00:00:06.900 is using to process this exact sentence right 00:00:06.900 --> 00:00:09.640 now doesn't actually come from firing a signal? 00:00:09.820 --> 00:00:11.679 Right, which is what we always assume. Yeah, 00:00:11.679 --> 00:00:15.259 exactly. It actually comes from the violent microscopic 00:00:15.259 --> 00:00:17.820 resetting of a trap afterward. I mean, just think 00:00:17.820 --> 00:00:20.000 about that for a second. You reach out for a 00:00:20.000 --> 00:00:23.980 cup of coffee, or you form a thought, you take 00:00:23.980 --> 00:00:26.239 a breath. It all feels perfectly seamless to 00:00:26.239 --> 00:00:28.800 you. Totally seamless. But underneath that smooth 00:00:28.800 --> 00:00:33.460 surface, Everything you do is driven by literally 00:00:33.460 --> 00:00:36.640 millions of molecular springs violently snapping 00:00:36.640 --> 00:00:39.539 shut and then being ripped back open inside your 00:00:39.539 --> 00:00:42.939 cells. It's a staggering reality to wrap your 00:00:42.939 --> 00:00:44.840 head around, honestly. Yeah. Because we only 00:00:44.840 --> 00:00:47.119 ever experience the final polished result, right? 00:00:47.439 --> 00:00:50.340 A muscle twitch or a sudden memory. Yeah. But 00:00:50.340 --> 00:00:52.500 the sheer logistical nightmare required to make 00:00:52.500 --> 00:00:54.299 those things happen on a cellular level is, I 00:00:54.299 --> 00:00:56.119 mean, it's an absolute master class in physics 00:00:56.119 --> 00:00:58.640 and engineering. And today we are going to look 00:00:58.640 --> 00:01:01.380 under the hood at that exact engineering. We 00:01:01.380 --> 00:01:04.459 are doing a deep dive into a massive, highly 00:01:04.459 --> 00:01:08.500 detailed Wikipedia article covering this really 00:01:08.500 --> 00:01:10.959 fascinating family of microscopic machines called 00:01:10.959 --> 00:01:14.420 snare proteins. Yes, snare proteins. Right. And 00:01:14.420 --> 00:01:16.680 our source material outlines everything here, 00:01:17.120 --> 00:01:19.299 from their physical architecture to how they 00:01:19.299 --> 00:01:23.739 function and even how they can be Lethally hijacked. 00:01:24.099 --> 00:01:25.819 And understanding these proteins, it's so much 00:01:25.819 --> 00:01:28.180 more than just an exercise in abstract biology. 00:01:28.879 --> 00:01:31.280 We're essentially talking about the ultimate 00:01:31.280 --> 00:01:33.379 shipping and receiving department of your body. 00:01:33.500 --> 00:01:36.780 The logistics network. Exactly. These snare proteins 00:01:36.780 --> 00:01:39.140 are the machines that allow tiny cellular shipping 00:01:39.140 --> 00:01:41.920 containers, which are called vesicles, to actually 00:01:41.920 --> 00:01:44.219 fuse with their destinations. So to understand 00:01:44.219 --> 00:01:47.000 how they work is to, well, understand the fundamental 00:01:47.000 --> 00:01:49.200 mechanics of human survival. OK, let's unpack 00:01:49.200 --> 00:01:51.700 this. Because if we want to understand how we're 00:01:51.629 --> 00:01:53.489 cells are actually communicating and sending 00:01:53.489 --> 00:01:56.390 these tiny packages to one another across microscopic 00:01:56.390 --> 00:01:59.349 distances, we really have to visualize the docking 00:01:59.349 --> 00:02:01.829 station they use. Right. And for a long time, 00:02:01.930 --> 00:02:04.730 the scientific community categorized this docking 00:02:04.730 --> 00:02:07.430 machinery purely based on geography. Like where 00:02:07.430 --> 00:02:10.569 they were located. Yeah, exactly. You had V -snares, 00:02:10.789 --> 00:02:12.849 which were built into the membrane of the transport 00:02:12.849 --> 00:02:15.789 vesicle itself. hence the V for vesicle. And 00:02:15.789 --> 00:02:18.930 then you had key snares, which sat entirely on 00:02:18.930 --> 00:02:21.069 the target membrane just waiting to receive that 00:02:21.069 --> 00:02:23.210 incoming vesicle. OK. But I noticed the source 00:02:23.210 --> 00:02:25.669 mentions a shift in how they classify these now. 00:02:25.849 --> 00:02:27.849 Instead of V and T, we are talking about R snares 00:02:27.849 --> 00:02:32.810 and Q snares. So why the upgrade in the naming 00:02:32.810 --> 00:02:35.370 convention? Well, what's fascinating here is 00:02:35.370 --> 00:02:37.750 that the new classification is based on their 00:02:37.750 --> 00:02:40.370 actual atomic building blocks rather than just 00:02:40.370 --> 00:02:42.819 where they happen to live. Because to form a 00:02:42.819 --> 00:02:44.939 successful connection, these proteins have to 00:02:44.939 --> 00:02:47.300 log together perfectly. Right. So an R snare 00:02:47.300 --> 00:02:50.139 -like, a protein called synaptobrevin, acts like 00:02:50.139 --> 00:02:52.680 a very specific peg. It contributes an amino 00:02:52.680 --> 00:02:55.039 acid called arginine, which biochemists represent 00:02:55.039 --> 00:02:57.240 with the letter R. Ah, OK. That makes sense. 00:02:57.340 --> 00:02:59.479 And on the other side, a Q snare -like, the protein 00:02:59.479 --> 00:03:02.900 syntaxin, an SNAP25, contributes an amino acid 00:03:02.900 --> 00:03:04.939 called glutamine, which is represented by Q. 00:03:05.080 --> 00:03:07.659 So it's essentially a molecular combination lock. 00:03:07.800 --> 00:03:10.219 You need the R components and the Q components 00:03:10.219 --> 00:03:13.099 to come together in exactly the right ratio to 00:03:13.099 --> 00:03:15.960 make it work. Precisely. Usually the R snares 00:03:15.960 --> 00:03:18.560 are riding on the vesicle and the Q snares are 00:03:18.560 --> 00:03:20.889 waiting on the target membrane. And when the 00:03:20.889 --> 00:03:23.469 vesicle gets close enough, these proteins literally 00:03:23.469 --> 00:03:25.849 reach out and intertwine. They grab each other. 00:03:25.909 --> 00:03:28.150 Yeah, forming what is known as a trans -snare 00:03:28.150 --> 00:03:31.449 complex. They create a bundle of four alpha helices. 00:03:32.169 --> 00:03:33.949 And you can think of an alpha helix kind of like 00:03:33.949 --> 00:03:36.770 a coiled spring. Okay, so four springs, where 00:03:36.770 --> 00:03:39.099 do they all come from? Well, Syntaxon provides 00:03:39.099 --> 00:03:41.860 one spring, Synaptobrevin provides another, and 00:03:41.860 --> 00:03:44.919 STMP -25 actually brings two to the party. Oh, 00:03:45.020 --> 00:03:47.919 wow. Yeah. And they all twist together into this 00:03:47.919 --> 00:03:51.080 incredibly dense four -stranded rope. I've been 00:03:51.080 --> 00:03:54.340 picturing this whole setup like a spacecraft 00:03:54.340 --> 00:03:56.500 docking with the International Space Station. 00:03:56.599 --> 00:03:58.580 That's a great way to look at it. Right, you 00:03:58.580 --> 00:04:00.840 have these two completely separate bodies floating 00:04:00.840 --> 00:04:03.460 in an abyss and they have to align perfectly, 00:04:03.780 --> 00:04:06.139 throw out the grappling hooks, and winch themselves 00:04:06.139 --> 00:04:09.840 together. But inside that four -stranded rope... 00:04:09.930 --> 00:04:12.530 Inside the docking hatch of our cellular space 00:04:12.530 --> 00:04:15.330 station, basically, there is this highly protected 00:04:15.330 --> 00:04:18.649 area called the zero ionic layer. Yeah, the zero 00:04:18.649 --> 00:04:20.689 ionic layer. That is the absolute core of the 00:04:20.689 --> 00:04:23.250 complex. It's where that one arginine and those 00:04:23.250 --> 00:04:28.149 three glutamines finally meet and lock the whole 00:04:28.149 --> 00:04:30.310 structure together through electrical charges. 00:04:30.430 --> 00:04:31.970 But here's where I get a little stuck on the 00:04:31.970 --> 00:04:33.889 architecture because the material points out 00:04:33.889 --> 00:04:36.610 that this ultra sensitive zero ionic layer is 00:04:36.610 --> 00:04:38.949 completely surrounded and guarded by watertight 00:04:38.949 --> 00:04:41.389 layers. Right, the leucine zippers. Yes, the 00:04:41.389 --> 00:04:43.990 leucine zippers. But if the electrical connection 00:04:43.990 --> 00:04:46.410 at the center is the most important part of the 00:04:46.410 --> 00:04:50.069 entire docking sequence, why deliberately hide 00:04:50.069 --> 00:04:52.290 it inside a watertight seal? Well, if we connect 00:04:52.290 --> 00:04:54.790 this to the bigger picture of how a cell survives, 00:04:55.250 --> 00:04:57.670 that watertight seal is actually the key to the 00:04:57.670 --> 00:05:00.509 whole operation. Water is incredibly disruptive 00:05:00.509 --> 00:05:02.509 to electrical charge. Oh sure, because it would 00:05:02.509 --> 00:05:05.689 short it out. Exactly. The leucine zipper acts 00:05:05.689 --> 00:05:08.069 like heavy rubber insulation around a copper 00:05:08.069 --> 00:05:11.310 wire, shielding that delicate ionic connection 00:05:11.310 --> 00:05:13.149 from the watery fluid of the rest of the cell. 00:05:13.709 --> 00:05:17.290 But here's the absolute genius of it. If you 00:05:17.290 --> 00:05:20.750 manage to break that seal and let water rush 00:05:20.750 --> 00:05:24.689 into the zero ionic layer, the entire snare complex 00:05:24.689 --> 00:05:27.889 becomes violently unstable. Oh, wow. So the cell 00:05:27.889 --> 00:05:30.310 engineers a self -destruct mechanism right into 00:05:30.310 --> 00:05:32.730 the center of the docking station. It's an engineered 00:05:32.730 --> 00:05:35.459 vulnerability. That instability isn't a flaw, 00:05:35.699 --> 00:05:38.769 it's a feature. As we'll see, introducing water 00:05:38.769 --> 00:05:41.970 into that core is the exact trick the cell uses 00:05:41.970 --> 00:05:44.430 to tear the incredibly tight docking station 00:05:44.430 --> 00:05:47.209 apart later, so it can recycle the parts for 00:05:47.209 --> 00:05:49.410 the next shipment. That is brilliant. The destruction 00:05:49.410 --> 00:05:51.750 is just built into the design. It really is. 00:05:51.810 --> 00:05:53.470 But let's look at the actual physics of this, 00:05:53.709 --> 00:05:55.569 because cell membranes are mostly covered in 00:05:55.569 --> 00:05:58.589 fatty lipids, and fat and fat naturally repel 00:05:58.589 --> 00:06:00.370 each other. Right, they really do not want to 00:06:00.370 --> 00:06:03.110 merge. So how does this twisting rope of proteins 00:06:03.110 --> 00:06:05.970 generate enough physical force to literally to 00:06:05.970 --> 00:06:08.889 mash two repelling membranes together. The physics 00:06:08.889 --> 00:06:12.449 of membrane fusion is basically an exercise in 00:06:12.449 --> 00:06:15.870 escalating tension. It happens in phases. First, 00:06:15.949 --> 00:06:18.290 there's an assembly phase, which is heavily monitored 00:06:18.290 --> 00:06:20.970 by the cell. Monitor how? Well, there's this 00:06:20.970 --> 00:06:24.189 chaperone protein called Monk 18, and it basically 00:06:24.189 --> 00:06:27.310 holds syntax in a closed state. It keeps the 00:06:27.310 --> 00:06:29.550 protein folded up so it can't accidentally start 00:06:29.550 --> 00:06:31.430 grabbing things floating by. Kind of like keeping 00:06:31.430 --> 00:06:34.389 the safety on. Exactly. When the proper signal 00:06:34.389 --> 00:06:37.569 arrives, MONC -18 releases syntaxin and actually 00:06:37.569 --> 00:06:39.970 helps it reach out to the other proteins. It 00:06:39.970 --> 00:06:42.110 acts as a catalyst to get the whole zippering 00:06:42.110 --> 00:06:45.089 process moving. And once MONC -18 gives the green 00:06:45.089 --> 00:06:47.149 light, we get something called the snare zippering 00:06:47.149 --> 00:06:50.069 hypothesis. Right. So as the helices from the 00:06:50.069 --> 00:06:52.310 vesicle and the target membrane grab each other, 00:06:52.629 --> 00:06:54.829 they start winding tighter and tighter. They 00:06:54.829 --> 00:06:57.209 literally zipper up from the top down to the 00:06:57.209 --> 00:06:59.170 membrane basis. Like twisting a rubber band. 00:06:59.329 --> 00:07:02.329 Yes. And as they twist, they store massive amounts 00:07:02.329 --> 00:07:05.689 of mechanical bending stress. The energy of them 00:07:05.689 --> 00:07:07.949 wanting to bind together translates into this 00:07:07.949 --> 00:07:10.750 intense brute force physical tension. And that 00:07:10.750 --> 00:07:13.509 tension is what finally overcomes the electrostatic 00:07:13.509 --> 00:07:16.189 repulsion of the two membranes pushing against 00:07:16.189 --> 00:07:19.649 each other. It is. It forces them so close that 00:07:19.649 --> 00:07:22.269 the membranes have no choice but to start interacting. 00:07:22.879 --> 00:07:25.519 And this brings us to a highly unstable moment 00:07:25.519 --> 00:07:29.160 called the splayed lipid state. The splayed lipid 00:07:29.160 --> 00:07:31.259 state? What does that look like? Well, the lipids 00:07:31.259 --> 00:07:33.420 in the outer layer of the vesicle membrane and 00:07:33.420 --> 00:07:36.000 the outer layer of the target membrane are smashed 00:07:36.000 --> 00:07:38.639 together so hard that they essentially swap partners. 00:07:39.360 --> 00:07:41.959 They put one foot in their own membrane and one 00:07:41.959 --> 00:07:44.639 foot into the neighboring membrane. Just casually 00:07:44.639 --> 00:07:46.879 stepping across the physical divide to form a 00:07:46.879 --> 00:07:50.860 bridge. Exactly. That bridge creates a tiny flickering 00:07:50.860 --> 00:07:53.439 stock between the two surfaces. And eventually 00:07:53.439 --> 00:07:56.420 that stock widens, opening up into a full fusion 00:07:56.420 --> 00:07:58.860 pore. And then it's open. The two membranes are 00:07:58.860 --> 00:08:01.899 now one continuous surface, and the entire chemical 00:08:01.899 --> 00:08:04.439 payload of the vesicle, which could be vital 00:08:04.439 --> 00:08:06.680 neurotransmitters, is dumped out of the cell. 00:08:06.879 --> 00:08:08.879 And at this point, all those snare proteins that 00:08:08.879 --> 00:08:11.019 were reaching across the gap are now just tangled 00:08:11.019 --> 00:08:12.800 together in the same single membrane, right? 00:08:12.990 --> 00:08:16.009 Yeah, which the material calls a cis -snare complex. 00:08:16.230 --> 00:08:18.550 Right. But I have to admit, I was completely 00:08:18.550 --> 00:08:21.689 wrong about how the energy here works. I assume 00:08:21.689 --> 00:08:24.290 there is some sort of biological battery sparking 00:08:24.290 --> 00:08:27.009 at the exact moment of impact to force the fusion. 00:08:27.629 --> 00:08:30.029 But it seems like the fusion itself is just the 00:08:30.029 --> 00:08:32.730 release of tension. Yeah, this brings us back 00:08:32.730 --> 00:08:34.289 to your opening thought about where the brain 00:08:34.289 --> 00:08:38.250 gets its energy. The actual smashing of the membranes 00:08:38.250 --> 00:08:40.730 is an energy -releasing event. Like letting go 00:08:40.730 --> 00:08:43.519 of a stretched rubber band. Exactly. The proteins 00:08:43.519 --> 00:08:45.919 naturally want to twist into that lower energy 00:08:45.919 --> 00:08:49.279 cis -snare complex. The real energy investment, 00:08:49.440 --> 00:08:51.539 the biological battery you're looking for, happens 00:08:51.539 --> 00:08:55.000 afterward. To reset the trap. Yes, exactly. Because 00:08:55.000 --> 00:08:57.759 the cell now has a useless tangled knot of snare 00:08:57.759 --> 00:09:00.139 proteins just stuck in his membrane. So to get 00:09:00.139 --> 00:09:02.460 them ready to fire again, it brings in a massive 00:09:02.460 --> 00:09:05.669 machine called NSF. which is an ATPase, along 00:09:05.669 --> 00:09:08.289 with a helper protein called alpha SNP. And they 00:09:08.289 --> 00:09:10.490 provide the energy. They burn cellular energy, 00:09:10.649 --> 00:09:13.110 known as ATP, to physically wrench that complex 00:09:13.110 --> 00:09:15.450 apart, breaking that watertight seal we talked 00:09:15.450 --> 00:09:17.809 about earlier. So they rip the zippers open, 00:09:18.190 --> 00:09:20.909 separate the pieces, and leave them hanging there 00:09:20.909 --> 00:09:23.590 in a high -energy spring -loaded state just waiting 00:09:23.590 --> 00:09:26.289 for the next signal. The source used an analogy 00:09:26.289 --> 00:09:28.629 of cocking a gun, which makes total sense now. 00:09:28.850 --> 00:09:31.330 It really does. You spend your energy pulling 00:09:31.330 --> 00:09:33.509 the hammer back so that when you need to fire, 00:09:33.610 --> 00:09:35.870 all you have to do is release the tension. It 00:09:35.870 --> 00:09:39.289 is an incredibly elegant lightning fast system. 00:09:39.570 --> 00:09:41.389 Here's where it gets really interesting though. 00:09:41.789 --> 00:09:44.750 If we are walking around with millions of these 00:09:44.750 --> 00:09:47.669 microscopic spring -loaded bear traps in our 00:09:47.669 --> 00:09:50.990 heads just waiting to violently pull membranes 00:09:50.990 --> 00:09:54.149 together, how do they not go off by accident? 00:09:54.289 --> 00:09:56.070 Right, because a misfire seems like it would 00:09:56.070 --> 00:09:59.590 be catastrophic. Yeah. Well... Regulation is 00:09:59.590 --> 00:10:02.169 everything here. If these traps fired randomly, 00:10:02.669 --> 00:10:04.970 your neurons could dump all their neurotransmitters 00:10:04.970 --> 00:10:07.029 constantly, and your nervous system would fry 00:10:07.029 --> 00:10:08.870 itself in seconds. So the body has to keep them 00:10:08.870 --> 00:10:11.149 in check? The body goes to extreme lengths to 00:10:11.149 --> 00:10:14.570 keep the brakes on. Let's take SN25, which is 00:10:14.570 --> 00:10:17.169 one of our key cue snares. Unlike the other proteins 00:10:17.169 --> 00:10:19.889 in this complex, SN25 doesn't have a built -in 00:10:19.889 --> 00:10:22.309 anchor. It doesn't naturally embed itself into 00:10:22.309 --> 00:10:24.580 the cell membrane. Wait, if it doesn't have an 00:10:24.580 --> 00:10:26.799 anchor, how does it not just float away into 00:10:26.799 --> 00:10:29.799 the cellular fluid? The cell uses a process called 00:10:29.799 --> 00:10:33.259 palmitoylation. It sounds complex, but it's basically 00:10:33.259 --> 00:10:35.659 a chemical stapler. A chemical stapler? I like 00:10:35.659 --> 00:10:37.740 that. Yeah, an enzyme takes fatty acid chains 00:10:37.740 --> 00:10:41.840 and specifically attaches them to SMED25. Those 00:10:41.840 --> 00:10:43.960 fatty chains act like anchors that sink deep 00:10:43.960 --> 00:10:46.440 into the lipid membrane, permanently tethering 00:10:46.440 --> 00:10:48.860 SNM25 exactly where the trap needs to be set. 00:10:49.000 --> 00:10:51.360 OK, so it's tied down, but what stops it from 00:10:51.360 --> 00:10:53.559 zippering up prematurely? Because I love the 00:10:53.559 --> 00:10:55.539 visual the material gives for this, focusing 00:10:55.539 --> 00:10:58.399 on syntaxin. The HABIC domain. Yes. Syntaxin 00:10:58.399 --> 00:11:01.179 has the snare domain that desperately wants to 00:11:01.179 --> 00:11:03.320 twist together with the others, but it also has 00:11:03.320 --> 00:11:05.559 this distinct section called the HABIC domain. 00:11:05.879 --> 00:11:08.700 And this domain literally folds backward over 00:11:08.700 --> 00:11:11.200 the protein, creating a physical shield. It blocks 00:11:11.200 --> 00:11:13.779 it completely. I picture it like a massive bouncer 00:11:13.779 --> 00:11:15.720 at a club, standing directly in front of the 00:11:15.720 --> 00:11:18.519 door, completely hiding the snare motif so nobody 00:11:18.519 --> 00:11:20.399 can interact with it until the bouncer steps 00:11:20.399 --> 00:11:23.480 aside. The bouncer analogy is perfect because 00:11:23.480 --> 00:11:25.779 it highlights how tightly controlled the timing 00:11:25.779 --> 00:11:29.200 is. But this raises an important question. What 00:11:29.200 --> 00:11:32.080 happens if that dimmer switch or that bouncer 00:11:32.080 --> 00:11:35.220 is slightly defective? Right. Because we aren't 00:11:35.220 --> 00:11:37.519 just talking about abstract cellular mechanics 00:11:37.519 --> 00:11:40.340 anymore. We are talking about human behavior. 00:11:40.519 --> 00:11:43.360 Right, because the material directly links slight 00:11:43.360 --> 00:11:46.379 variations in these proteins to major psychiatric 00:11:46.379 --> 00:11:49.720 conditions. See, SNF25 doesn't just sit there 00:11:49.720 --> 00:11:53.039 waiting to form a complex. It moonlights as a 00:11:53.039 --> 00:11:55.139 regulator for voltage -gated calcium channels. 00:11:55.419 --> 00:11:58.080 And calcium is the trigger signal. Exactly. Calcium 00:11:58.080 --> 00:12:00.379 is the signal that tells the snare trap to spring. 00:12:01.420 --> 00:12:03.919 SNF25 acts like a governor on that calcium channel, 00:12:04.299 --> 00:12:06.299 controlling how much signal gets through. If 00:12:06.299 --> 00:12:09.139 you alter SNF25, you alter the flow of calcium, 00:12:09.580 --> 00:12:11.860 which means neurotransmitters are released erratically. 00:12:11.950 --> 00:12:14.210 And the clinical side of that is wild. Studies 00:12:14.210 --> 00:12:17.230 show that variations in the SNF25 gene are strongly 00:12:17.230 --> 00:12:19.909 linked to attention deficit hyperactivity disorder, 00:12:20.350 --> 00:12:23.029 or ADHD. It's a direct link. They even bred mice 00:12:23.029 --> 00:12:25.809 entirely lacking certain SNF25 functions, and 00:12:25.809 --> 00:12:28.169 the mice exhibit classic hyperactivity phenotypes. 00:12:28.509 --> 00:12:32.389 And it extends way beyond hyperactivity. Altered 00:12:32.389 --> 00:12:35.250 expression of these exact proteins has been correlated 00:12:35.250 --> 00:12:38.769 with the onset of schizophrenia and autism spectrum 00:12:38.769 --> 00:12:42.009 disorders. Really? Yes. Think about what schizophrenia 00:12:42.009 --> 00:12:44.570 entails. Differences in perception, processing, 00:12:44.789 --> 00:12:47.509 and signaling. If the physical machinery that 00:12:47.509 --> 00:12:50.570 releases neurotransmitters is misfiring, the 00:12:50.570 --> 00:12:53.629 downstream effect is a profound alteration of 00:12:53.629 --> 00:12:55.629 human consciousness. There's another protein 00:12:55.629 --> 00:12:58.399 mentioned, Syntaxin 1b. which manages something 00:12:58.399 --> 00:13:01.120 called the readily -releasable pool of vesicles. 00:13:01.320 --> 00:13:05.000 Ah, the RRP. Yeah. It's essentially the neuron's 00:13:05.000 --> 00:13:07.539 ammo clip, the vesicles that are docked and fully 00:13:07.539 --> 00:13:10.139 ready to fire the exact second of thought forms. 00:13:10.649 --> 00:13:13.649 If syntax in 1B is compromised, that ammo clip 00:13:13.649 --> 00:13:16.350 shrinks. It just doesn't have the capacity. Exactly. 00:13:16.549 --> 00:13:18.830 It's fascinating and honestly a little unsettling 00:13:18.830 --> 00:13:22.090 to realize that complex human psychiatric conditions 00:13:22.090 --> 00:13:25.009 can be rooted in the mechanical failure of microscopic 00:13:25.009 --> 00:13:27.370 springs and zippers. It perfectly illustrates 00:13:27.370 --> 00:13:30.490 how macro level human experience is entirely 00:13:30.490 --> 00:13:32.830 dependent on micro level physics. Which naturally 00:13:32.830 --> 00:13:35.049 leads us to a much darker question. I think I 00:13:35.049 --> 00:13:36.750 know where you're going with this. If the body 00:13:36.750 --> 00:13:39.950 goes to such extreme convoluted lengths to build 00:13:39.950 --> 00:13:43.110 place and guard these traps. What happens if 00:13:43.110 --> 00:13:46.110 an outside invader figures out how to disarm 00:13:46.110 --> 00:13:48.470 them? You're referring to the molecular saboteurs. 00:13:49.539 --> 00:13:51.879 Botulinum neurotoxin and tetanus neurotoxin. 00:13:51.899 --> 00:13:54.259 The heavy hitters. Oh, absolutely. These are 00:13:54.259 --> 00:13:57.799 two of the most infamous deadly biological substances 00:13:57.799 --> 00:14:00.919 ever discovered by science. And their entire 00:14:00.919 --> 00:14:03.620 evolutionary strategy is focused exclusively 00:14:03.620 --> 00:14:06.379 on destroying snare proteins. They bypass everything 00:14:06.379 --> 00:14:08.379 else in the body and go straight for the docking 00:14:08.379 --> 00:14:11.580 station. Yes. Both of these toxins utilize a 00:14:11.580 --> 00:14:14.659 very similar brutal two -part structure. They're 00:14:14.659 --> 00:14:17.440 made of a heavy chain and a light chain. tied 00:14:17.440 --> 00:14:19.799 together by a chemical bond. As I understand 00:14:19.799 --> 00:14:22.039 it, the heavy chain is basically the lockpick. 00:14:22.139 --> 00:14:23.860 That's a good way to put it. It's the delivery 00:14:23.860 --> 00:14:26.940 vehicle that finds a specific nerve ending, binds 00:14:26.940 --> 00:14:29.500 to the outside, and kind of tricks the neuron 00:14:29.500 --> 00:14:32.000 into swallowing the toxin whole. And once it's 00:14:32.000 --> 00:14:34.620 swallowed, it drops the payload. The heavy chain 00:14:34.620 --> 00:14:36.799 pushes the light chain out into the main fluid 00:14:36.799 --> 00:14:39.600 of the cell. And the light chain is the actual 00:14:39.600 --> 00:14:42.240 weapon. What does it do? It's a highly specialized 00:14:42.240 --> 00:14:45.820 enzyme. a zinc -dependent endopeptidase. I was 00:14:45.820 --> 00:14:47.960 trying to visualize how it attacks. We talked 00:14:47.960 --> 00:14:50.600 about the snare complex being like a loaded mousetrap. 00:14:50.940 --> 00:14:53.059 Is the light chain acting like a saboteur who 00:14:53.059 --> 00:14:55.039 sneaks in and just, you know, cuts the retaining 00:14:55.039 --> 00:14:58.120 pin? It is exactly what it does. It chemically 00:14:58.120 --> 00:15:00.620 cleaves the snare proteins in half so they can 00:15:00.620 --> 00:15:03.220 never zipper up. But what's terrifying is how 00:15:03.220 --> 00:15:05.759 specific they are. Specific to certain proteins? 00:15:05.919 --> 00:15:09.879 Yeah. Botulinum neurotoxin, or BONT, goes after 00:15:09.879 --> 00:15:14.580 SNF25. Syntaxin 1 and the vesicle protein VAMP2. 00:15:14.820 --> 00:15:18.059 Tetanus neurotoxin, or TENTY, specifically hunts 00:15:18.059 --> 00:15:20.500 down and shreds syneptobrevin. But the end result 00:15:20.500 --> 00:15:22.919 is the same, regardless of which piece they cut. 00:15:23.200 --> 00:15:25.120 Completely the same. Right, because if the biological 00:15:25.120 --> 00:15:27.360 zip ties are severed, the vesicles are permanently 00:15:27.360 --> 00:15:30.019 stranded. They can't fuse, the neurotransmitters 00:15:30.019 --> 00:15:32.440 are trapped inside the cell, and the signal goes 00:15:32.440 --> 00:15:35.240 completely dead. Which leads to muscle paralysis, 00:15:35.659 --> 00:15:37.919 spasms, and if it hits your respiratory system, 00:15:38.220 --> 00:15:41.639 death. Yeah. But I have to ask a deeply practical 00:15:41.639 --> 00:15:43.379 question here on behalf of anyone listening. 00:15:44.120 --> 00:15:46.980 If botulinum is recognized as the most potent 00:15:46.980 --> 00:15:50.320 lethal toxin ever discovered, and its sole purpose 00:15:50.320 --> 00:15:52.600 is to permanently sever our neural connections, 00:15:53.279 --> 00:15:56.679 why on earth are millions of people happily injecting 00:15:56.679 --> 00:15:59.740 it into their foreheads? It sounds totally absurd 00:15:59.740 --> 00:16:02.500 until you understand the mechanics of dose dependency. 00:16:02.700 --> 00:16:06.120 It is all about localized versus systemic application. 00:16:06.299 --> 00:16:09.120 Okay, break that down for me. If you ingest botulinum 00:16:09.120 --> 00:16:11.480 from a tainted can of food, it enters your bloodstream. 00:16:12.039 --> 00:16:14.600 It circulates systemically, finds its way to 00:16:14.600 --> 00:16:16.879 the nerves controlling your diaphragm, severs 00:16:16.879 --> 00:16:19.899 the snare proteins, and you suffocate. That is 00:16:19.899 --> 00:16:22.500 fatal. But Botox is different. Right. When a 00:16:22.500 --> 00:16:24.940 doctor uses Bococks cosmetically or medically, 00:16:25.240 --> 00:16:27.399 they are taking an astronomically small, highly 00:16:27.399 --> 00:16:29.799 diluted amount of the toxin and injecting it 00:16:29.799 --> 00:16:32.399 into a very specific, isolated muscle fiber in 00:16:32.399 --> 00:16:34.820 the face. So it doesn't spread? Exactly. It enters 00:16:34.820 --> 00:16:37.340 those local nerve endings and cuts the snare 00:16:37.340 --> 00:16:39.740 proteins just in that one millimeter of tissue. 00:16:40.679 --> 00:16:43.019 The localized muscle can't receive the signal 00:16:43.019 --> 00:16:45.659 to contract, so it relaxes, smoothing out the 00:16:45.659 --> 00:16:47.840 wrinkle. Because it doesn't travel through the 00:16:47.840 --> 00:16:50.480 bloodstream, your diaphragm is perfectly safe. 00:16:50.730 --> 00:16:53.950 It is weaponized biology applied with surgical 00:16:53.950 --> 00:16:57.169 precision. That is incredible. We've taken nature's 00:16:57.169 --> 00:17:00.090 ultimate saboteur and turned it into a localized 00:17:00.090 --> 00:17:02.759 volume knob. for muscle tension. That's a great 00:17:02.759 --> 00:17:04.500 way to describe it. But I want to zoom out for 00:17:04.500 --> 00:17:06.680 a second. We've spent this entire time talking 00:17:06.680 --> 00:17:09.400 about neurons, synapses, and brain function. 00:17:10.019 --> 00:17:12.960 But if a cell has perfected this incredibly efficient 00:17:12.960 --> 00:17:15.819 way to merge two separate compartments, does 00:17:15.819 --> 00:17:18.400 it use that trick anywhere else? Oh, absolutely. 00:17:18.819 --> 00:17:21.359 Snares are not unique to the human brain. They 00:17:21.359 --> 00:17:23.859 are a fundamental building block of eukaryotic 00:17:23.859 --> 00:17:26.049 life. So they're everywhere. They are operating 00:17:26.049 --> 00:17:28.609 right now in your liver cells in yeast in the 00:17:28.609 --> 00:17:31.630 roots of plants. One of their most critical functions 00:17:31.630 --> 00:17:34.589 outside the nervous system is in a process called 00:17:34.589 --> 00:17:37.230 macro autophagy. Which is cellular recycling, 00:17:37.430 --> 00:17:39.569 right? The cell literally eating parts of itself 00:17:39.569 --> 00:17:42.569 to clear out damaged proteins and old organelles. 00:17:42.769 --> 00:17:44.750 Exactly. When a cell spots a piece of garbage, 00:17:45.329 --> 00:17:47.730 it builds a double membrane bag around it called 00:17:47.730 --> 00:17:50.460 on autophagosome. But an autophaxome is just 00:17:50.460 --> 00:17:52.119 a trash bag. It can't destroy anything on its 00:17:52.119 --> 00:17:54.380 own. So it needs an incinerator. Right. It has 00:17:54.380 --> 00:17:56.859 to physically fuse with a lysosome, which is 00:17:56.859 --> 00:17:59.359 essentially a cellular incinerator packed with 00:17:59.359 --> 00:18:01.680 destructive enzymes. And merging the trash bag 00:18:01.680 --> 00:18:04.000 with the incinerator requires the exact same 00:18:04.000 --> 00:18:06.259 brute force zippering physics we just talked 00:18:06.259 --> 00:18:09.039 about. It relies entirely on a specific set of 00:18:09.039 --> 00:18:12.799 snare proteins, including VMV7 and Syntaxin 7. 00:18:13.099 --> 00:18:15.099 But the star of this particular show is a protein 00:18:15.099 --> 00:18:18.910 called Syntaxin 17, or STX17. I was reading about 00:18:18.910 --> 00:18:22.849 STX 17 and it immediately made me wonder if the 00:18:22.849 --> 00:18:25.210 cell is building these internal garbage bags 00:18:25.210 --> 00:18:28.769 to incinerate waste, how does it stop the incinerator 00:18:28.769 --> 00:18:31.230 from turning on before the bag is fully sealed? 00:18:31.670 --> 00:18:33.410 You wouldn't want digestive enzymes spilling 00:18:33.410 --> 00:18:35.690 out into the healthy parts of the cell. No, you 00:18:35.690 --> 00:18:38.009 definitely wouldn't. And that is exactly what 00:18:38.009 --> 00:18:41.910 STX 17 prevents. It is an ingenious safety mechanism. 00:18:42.890 --> 00:18:46.329 STX17 refuses to bind to the outer membrane of 00:18:46.329 --> 00:18:48.809 the autophagosome while the bag is still being 00:18:48.809 --> 00:18:51.450 built. It waits. It only attaches itself once 00:18:51.450 --> 00:18:53.369 the structure is completely sealed and mature. 00:18:54.029 --> 00:18:57.109 It acts as the final confirmation signal. Only 00:18:57.109 --> 00:19:00.329 then can the snare complex zipper up and pull 00:19:00.329 --> 00:19:02.690 the incinerator into contact with the trash bag. 00:19:02.839 --> 00:19:05.099 And when that recycling system breaks down, the 00:19:05.099 --> 00:19:07.619 consequences are severe. There are lysosomal 00:19:07.619 --> 00:19:09.940 storage disorders where cholesterol builds up 00:19:09.940 --> 00:19:13.079 inside the lysosome. And from a mechanical standpoint, 00:19:13.279 --> 00:19:15.839 the excess cholesterol essentially traps the 00:19:15.839 --> 00:19:17.920 snare proteins deep in the membrane. They get 00:19:17.920 --> 00:19:19.960 completely stuck. Right. They get stuck. The 00:19:19.960 --> 00:19:21.680 cell can't pull them out to recycle them. And 00:19:21.680 --> 00:19:23.599 the entire waste management system of the cell 00:19:23.599 --> 00:19:26.480 just grinds to a halt. Which causes toxic buildup 00:19:26.480 --> 00:19:28.759 and eventually cellular death. OK, I have to 00:19:28.759 --> 00:19:30.599 push back a little here because everything we've 00:19:30.599 --> 00:19:33.569 outlined today. From the zero ionic layer needing 00:19:33.569 --> 00:19:36.569 a perfect watertight seal, to the highly specific 00:19:36.569 --> 00:19:40.250 bouncer proteins, to the vulnerability, to toxins, 00:19:40.529 --> 00:19:43.430 the cholesterol jamming the gears, it makes this 00:19:43.430 --> 00:19:46.349 whole system sound terrifyingly fragile. It really 00:19:46.349 --> 00:19:49.289 does. If one single microscopic peg is out of 00:19:49.289 --> 00:19:51.569 place, the whole machine catastrophically fails. 00:19:52.039 --> 00:19:54.920 Are we actually that fragile? You know, it is 00:19:54.920 --> 00:19:57.039 a completely natural conclusion to draw when 00:19:57.039 --> 00:19:59.279 you look at the sheer complexity of the interlocking 00:19:59.279 --> 00:20:01.859 parts, but the reality is actually the opposite. 00:20:02.279 --> 00:20:05.380 Evolution doesn't favor fragility. This system 00:20:05.380 --> 00:20:08.039 has an unbelievable level of resilience built 00:20:08.039 --> 00:20:10.980 into it through a concept called flexible substitution. 00:20:11.400 --> 00:20:13.960 Meaning there are backup systems in place. Massive 00:20:13.960 --> 00:20:16.039 redundancy. For example, if you take a fruit 00:20:16.039 --> 00:20:18.059 fly and completely delete the gene that makes 00:20:18.059 --> 00:20:20.720 SNF25, a component we just said, is absolutely 00:20:20.720 --> 00:20:23.910 vital for life, The fly doesn't die. Wait, really? 00:20:24.069 --> 00:20:27.349 It survives without SNF25? Yes. The cellular 00:20:27.349 --> 00:20:29.490 machinery immediately detects the missing piece 00:20:29.490 --> 00:20:32.329 and slots in a homologous backup protein called 00:20:32.329 --> 00:20:35.589 SNF4 to take its place. And yeast cells do the 00:20:35.589 --> 00:20:37.890 exact same thing, right? Yeah. If a yeast cell 00:20:37.890 --> 00:20:42.369 loses a critical R -snare called Sec22P, it upregulates 00:20:42.369 --> 00:20:45.289 a substitute called YAT6P, drops it into the 00:20:45.289 --> 00:20:47.910 assembly line, and the vesicle traffic just keeps 00:20:47.910 --> 00:20:50.710 flowing without missing a beat. It's not a franchise 00:20:50.710 --> 00:20:54.029 house of cards. It's a highly adaptable ancient 00:20:54.029 --> 00:20:57.210 mechanism that has survived billions of years 00:20:57.210 --> 00:21:00.089 of evolution. It really completely reframes how 00:21:00.089 --> 00:21:01.890 you think about your own physical existence. 00:21:02.009 --> 00:21:04.490 I mean, just sitting here having this conversation. 00:21:04.829 --> 00:21:08.029 Your ability to hear these words, to synthesize 00:21:08.029 --> 00:21:10.549 this information, is all being facilitated by 00:21:10.549 --> 00:21:13.289 millions of snare complexes zippering together. 00:21:13.410 --> 00:21:15.390 Yeah, overcoming the electrostatic repulsion 00:21:15.390 --> 00:21:18.150 of your membranes. Right. Spilling neurotransmitters 00:21:18.150 --> 00:21:20.529 across synapses, and then being violently ripped 00:21:20.529 --> 00:21:23.289 apart by ATP, all in a fraction of a millisecond. 00:21:23.450 --> 00:21:25.890 The scale, the speed, and the precision are truly 00:21:25.890 --> 00:21:27.769 humbling when you strip away the biology and 00:21:27.769 --> 00:21:29.970 just look at the raw mechanics of it. So what 00:21:29.970 --> 00:21:32.319 does this all mean? We started with the atomic 00:21:32.319 --> 00:21:35.079 structure of a microscopic coiled spring, and 00:21:35.079 --> 00:21:37.859 we've traced it all the way up to human consciousness, 00:21:38.279 --> 00:21:41.700 psychiatric diseases, and deadly saboteurs. Where 00:21:41.700 --> 00:21:44.440 does that leave us? Well, if we step back and 00:21:44.440 --> 00:21:47.160 look at the source material in totality, I want 00:21:47.160 --> 00:21:49.279 to leave you with a thought about the sheer diversity 00:21:49.279 --> 00:21:52.180 of these proteins. We've talked a lot about syntaxin 00:21:52.180 --> 00:21:54.900 today, but the human genome doesn't just code 00:21:54.900 --> 00:21:58.539 for one type of syntaxin. It contains 15 completely 00:21:58.539 --> 00:22:01.559 different varieties that single protein alone. 00:22:01.819 --> 00:22:04.579 15 variations of just one piece of the trap. 00:22:04.819 --> 00:22:08.259 Exactly. If a simple 4 -helix bundle can be customized 00:22:08.259 --> 00:22:10.460 and swapped out that many different ways across 00:22:10.460 --> 00:22:13.220 the human body, it heavily implies that there 00:22:13.220 --> 00:22:17.559 is a staggeringly complex hidden zip code system 00:22:17.559 --> 00:22:20.500 directing cellular traffic. A zip code system. 00:22:20.640 --> 00:22:23.099 A molecular routing system we're only just beginning 00:22:23.099 --> 00:22:25.970 to decipher. It really makes you wonder What 00:22:25.970 --> 00:22:28.369 other microscopic codes, what other physical 00:22:28.369 --> 00:22:30.710 algorithms are running quietly in the background 00:22:30.710 --> 00:22:33.130 of your own body right now, completely unnoticed? 00:22:33.210 --> 00:22:34.809 I don't think I'll ever look at a simple movement 00:22:34.809 --> 00:22:36.890 the same way again. The next time you casually 00:22:36.890 --> 00:22:39.029 reach for that cup of coffee, just take a second 00:22:39.029 --> 00:22:41.430 to appreciate the millions of molecular zippers 00:22:41.430 --> 00:22:44.230 violently springing shut and tearing apart just 00:22:44.230 --> 00:22:45.789 to let you wrap your fingers around the mug.