WEBVTT - Folding the Proteins 0:00:04.240 --> 0:00:07.200 Get in touch with technology with text stuff from how 0:00:07.240 --> 0:00:14.080 stuff works dot Com. Hey there, and welcome to tex Stuffs. 0:00:14.120 --> 0:00:17.720 I'm Jonathan Strickland and I'm Lauren Focon And we've got 0:00:17.800 --> 0:00:20.360 some some listener mail here that we need to read 0:00:20.400 --> 0:00:24.319 because it's going to launch us directly into this episode. Yes, 0:00:24.440 --> 0:00:27.640 this comes this from listener Caleb, who wrote in on 0:00:27.640 --> 0:00:30.960 Facebook and said, can you all research how biological proofs 0:00:31.040 --> 0:00:36.240 unfolding and how their computer algorithms work? And we sure 0:00:36.320 --> 0:00:39.960 can do that thing? We can and we did well well, 0:00:40.000 --> 0:00:43.640 I mean yes, we did. The research is in the past, 0:00:43.720 --> 0:00:46.440 the podcasting is in the immediate future. Yes, yes, has 0:00:46.479 --> 0:00:48.960 houses going to We're going to now podcast about the 0:00:48.960 --> 0:00:51.680 thing we've been researching. We're kind of delaying because, as 0:00:51.720 --> 0:00:54.280 it turns out, there's there's quite a bit of groundwork 0:00:54.320 --> 0:00:57.280 we have delay before we can get into the technology 0:00:57.520 --> 0:01:00.560 because just saying what the technology does doesn't really do 0:01:00.600 --> 0:01:03.920 it justice. You don't understand how complex the problem is 0:01:04.040 --> 0:01:08.240 until you understand the basics about proteins themselves. Right, Um, 0:01:08.440 --> 0:01:12.120 So let's talk first about what protein folding is and 0:01:12.240 --> 0:01:18.160 why it's so important because okay, so and this does 0:01:18.240 --> 0:01:21.440 have to do with technology, not not just the algorithm part, 0:01:21.560 --> 0:01:26.280 but biological technology. We're we're talking here about cellular programming, 0:01:26.319 --> 0:01:31.800 not like cell phone programming, but biological cells. Yes, Um, 0:01:32.200 --> 0:01:36.480 the software that tells living cells what to do are proteins. 0:01:36.600 --> 0:01:40.160 And proteins are strings or chains made up of different 0:01:40.160 --> 0:01:43.399 amino acids, depending on a bunch of different factors, like 0:01:43.600 --> 0:01:46.120 the structure of each amino acid in the chain, that 0:01:46.240 --> 0:01:49.280 the order of the amino acids in the chain, and 0:01:49.360 --> 0:01:53.280 the presence of little genetic bits that act like stop signals. Um, 0:01:53.360 --> 0:01:56.720 these chains come together and then fold up into these 0:01:56.760 --> 0:02:00.640 really complex three dimensional shapes, and once they're in those shapes, 0:02:00.960 --> 0:02:04.400 they can form structures or act as chemical catalysts to 0:02:04.440 --> 0:02:06.720 set off any of the functions of a cell. That 0:02:06.800 --> 0:02:11.320 they're directly responsible for life happening basically, so, so doctors 0:02:11.360 --> 0:02:13.679 and scientists are pretty interested in how they form. And 0:02:13.919 --> 0:02:16.400 you may be asking, all right, so what exactly I mean, 0:02:16.919 --> 0:02:19.120 you're giving me kind of a big picture, but what 0:02:19.200 --> 0:02:21.640 exactly are they responsible for? So here are just a 0:02:21.639 --> 0:02:25.200 few examples. Keep in mind this is not an exhaustive list, 0:02:25.280 --> 0:02:28.480 certainly not so supporting the skeleton that's a big deal 0:02:28.919 --> 0:02:30.720 for us. I mean we don't want to just be 0:02:30.800 --> 0:02:35.000 blobs of people. I mean sometimes I do, but sometimes 0:02:35.480 --> 0:02:39.399 downhill to just melt under my desk, That's true. There 0:02:39.400 --> 0:02:42.399 are there are those days. Then there's a there's controlling 0:02:42.440 --> 0:02:47.080 our senses. That's important. Obviously moving muscles. So even if 0:02:47.080 --> 0:02:49.400 you didn't have that skeleton, presumably you'd want to have 0:02:49.480 --> 0:02:52.440 some say over where you were going. I would. Yeah, 0:02:53.200 --> 0:02:57.959 Digesting food very important, that's actually my primary Yeah, I 0:02:58.360 --> 0:03:02.240 dedicate nearly seven percent of all brain power into figuring 0:03:02.320 --> 0:03:05.839 out where I'm going to get my food next. Then 0:03:06.080 --> 0:03:11.280 defending against infections very important to process emotions. So here's 0:03:11.280 --> 0:03:14.520 what it boils down to. If it's a biological function, 0:03:15.000 --> 0:03:18.360 you can bet proteins are involved in it in some fashion, 0:03:18.400 --> 0:03:22.840 and usually they're ultimately responsible for what's going on now. 0:03:23.000 --> 0:03:26.160 In nature, the way that a protein forms is through 0:03:26.200 --> 0:03:30.720 this process of linking together the appropriate amino acids. Right, 0:03:30.800 --> 0:03:34.080 these twenty different building blocks that can make up all 0:03:34.120 --> 0:03:37.640 these different types of proteins, and the sequence will determine 0:03:37.640 --> 0:03:40.720 what the function of the protein is. But the protein 0:03:40.800 --> 0:03:44.880 itself will not be functional until it's in its final shape, 0:03:44.880 --> 0:03:48.320 which is called the tertiary structure, so called because the 0:03:48.320 --> 0:03:52.080 protein folds into a secondary structure first, uh, and that's 0:03:52.120 --> 0:03:54.440 just a pretty simple one, one of a couple of 0:03:54.480 --> 0:03:59.280 different different possibilities before settling into its final three dimensional form. 0:04:00.000 --> 0:04:01.920 And then once you've got that three dimensional form, that's 0:04:01.920 --> 0:04:04.920 when the protein can do what it is supposed to do. Now, 0:04:05.840 --> 0:04:08.160 remember I said there were just twenty different amino acids, 0:04:08.560 --> 0:04:12.320 So those are your twenty basic building blocks. Now, so 0:04:12.360 --> 0:04:16.159 far we've identified more than a hundred thousand different proteins 0:04:16.200 --> 0:04:20.679 that are in human bodies alone, all made from those 0:04:21.360 --> 0:04:24.039 building blocks. Yeah, so it just means that all the 0:04:24.040 --> 0:04:27.599 different combinations. Some some of these proteins are relatively short, 0:04:28.000 --> 0:04:30.320 meaning that they might be a hundred or so amino 0:04:30.360 --> 0:04:32.720 acid blocks long. Some of them can be more than 0:04:32.760 --> 0:04:36.880 a thousand blocks long. So that means that, uh, it 0:04:36.920 --> 0:04:40.560 gets pretty complicated just based upon the sequence of amino acids. 0:04:40.600 --> 0:04:43.919 Then you have to think of the possible orientations those 0:04:43.960 --> 0:04:46.520 blocks can have in relation to each other during this 0:04:46.560 --> 0:04:49.920 whole folding process. Sure, and also I wanted to put 0:04:49.960 --> 0:04:53.720 in that protein misfolding, which can be caused by a 0:04:53.839 --> 0:04:56.880 number of factors as well. It is thought to cause 0:04:56.920 --> 0:05:00.880 health problems from allergies, to diseases likes to fibrosis, to 0:05:01.360 --> 0:05:04.560 most degenerative brain diseases like Alzheimer's, and this is all 0:05:04.640 --> 0:05:09.400 due to to flawed protein structures giving bad instructions to cells. Right, 0:05:10.480 --> 0:05:13.800 So what we're getting at here is that this is 0:05:13.920 --> 0:05:16.640 this is pretty complicated, right. Yeah. The shapes of these 0:05:16.680 --> 0:05:21.279 protein structures are incredibly difficult to predict because the language 0:05:21.320 --> 0:05:24.039 that they're coded in is really whibbly wobbly. The same 0:05:24.040 --> 0:05:25.800 way that you can say something in a lot of 0:05:25.839 --> 0:05:28.880 different ways in English, or you know, get a desired 0:05:28.920 --> 0:05:31.960 effect in photoshop through a lot of different options, or 0:05:32.120 --> 0:05:36.640 solve an equation through different methods, genetic code is redundant. 0:05:37.520 --> 0:05:41.000 The same amino acid can be built from different building blocks, 0:05:41.120 --> 0:05:44.320 and it's it's not it's not all a one to 0:05:44.440 --> 0:05:46.800 one ratio of it's not a it's not a one 0:05:46.839 --> 0:05:51.039 to one factor of how something's going to work. Right. Yeah, 0:05:51.320 --> 0:05:54.719 you can't easily predict just based upon like if I 0:05:54.720 --> 0:05:56.880 gave you a sequence of amino acids that made up 0:05:56.880 --> 0:06:00.359 a protein, you could not automatically say, oh, this is 0:06:00.360 --> 0:06:02.960 exactly how it's going to fauld because, like we were saying, 0:06:03.320 --> 0:06:05.880 there are lots, Yeah, there are a lot of potential 0:06:05.880 --> 0:06:08.159 ways that this can happen. Some of the shapes that 0:06:08.240 --> 0:06:11.760 you can encounter with proteins include round proteins that's like hemoglobin, 0:06:12.440 --> 0:06:16.279 long proteins collagen would be an example, strong proteins, which 0:06:16.440 --> 0:06:20.080 includes spectron that protects the cells that carry oxygen from 0:06:20.160 --> 0:06:23.000 our lungs to everywhere else it needs to go. Or 0:06:23.120 --> 0:06:27.040 elastic proteins like titan, which controls muscle stretching and contraction. 0:06:27.080 --> 0:06:30.040 And here's another fun fact. The chemical name for Titan 0:06:30.480 --> 0:06:36.680 is more than one hundred eighty nine thousand letters long. Yeah, 0:06:36.720 --> 0:06:38.960 it takes three and a half hours to pronounce the 0:06:39.000 --> 0:06:42.000 full chemical name for titan. I am not making this 0:06:42.120 --> 0:06:46.000 up three and a half hours, So here we go. No, 0:06:46.120 --> 0:06:48.000 I'm just kidding. We we've never done a three and 0:06:48.000 --> 0:06:50.200 a half hour long podcast. We will not be doing 0:06:50.200 --> 0:06:53.320 one today. But it is the largest protein we've identified 0:06:53.400 --> 0:06:56.680 so far, so I guess it it's entitled to a 0:06:56.800 --> 0:06:59.280 three and a half hour long name. There are, by 0:06:59.279 --> 0:07:02.760 the way, videos on YouTube that you can watch that 0:07:02.920 --> 0:07:06.159 have the full pronunciation three and a half hours. I'm 0:07:06.200 --> 0:07:07.960 glad that someone else has done that so that we 0:07:08.000 --> 0:07:09.760 don't have to. Yeah, it will try to link that 0:07:09.800 --> 0:07:11.920 out on social just in case you're curious. The one 0:07:11.960 --> 0:07:16.560 I watched was obviously a Russian person pronouncing it, because 0:07:16.600 --> 0:07:22.560 the the annunciation was very Russian. But he started off 0:07:22.800 --> 0:07:27.640 already looking pensive and bored before. I don't know if 0:07:27.680 --> 0:07:31.720 it was staged to like what he had. He had 0:07:31.720 --> 0:07:34.320 a nice little vase of flowers next to him, and 0:07:34.440 --> 0:07:36.760 I mean it was I didn't. I didn't watch all 0:07:36.760 --> 0:07:38.040 three and a half hours, so I don't know how 0:07:38.120 --> 0:07:39.800 much of it changed. I did see someone point out 0:07:39.800 --> 0:07:42.920 that there was a apparently an obvious cut in the 0:07:43.000 --> 0:07:46.640 video some two hours in. Give the guy a break, literally, 0:07:46.680 --> 0:07:50.600 give the guy a break, alright. So the sequence of 0:07:50.640 --> 0:07:53.000 amino acids makes it really easy to predict what the 0:07:53.040 --> 0:07:55.480 secondary structure of the protein will look like. That that 0:07:55.560 --> 0:07:59.240 intermediary step and that part is easy to predict. But 0:07:59.320 --> 0:08:02.200 what the fine old tertiary structure will be like is 0:08:02.200 --> 0:08:05.360 a totally different problem. And to learn that we have 0:08:05.400 --> 0:08:08.360 to do lots of experiments, and according to Nature dot com, 0:08:08.520 --> 0:08:11.680 we only have data on ten of all the proteins 0:08:11.680 --> 0:08:14.960 we've identified where we can reasonably say the way that 0:08:15.040 --> 0:08:17.840 they fold. Part of that is because you might say, well, 0:08:17.840 --> 0:08:19.960 Why don't we just look at the protein. Why don't 0:08:20.000 --> 0:08:21.640 we just look at it, then we can see how 0:08:21.640 --> 0:08:25.840 it folds where's the problem? It actually is an incredibly 0:08:25.880 --> 0:08:28.480 long process because these proteins are are made up of 0:08:28.480 --> 0:08:32.560 the very tiny components and they fold in on themselves. Right, 0:08:32.880 --> 0:08:35.600 So imagine that you just came up to a mass 0:08:35.760 --> 0:08:39.480 of string and it's all knotted up in a big wad. 0:08:40.320 --> 0:08:42.960 It'd be really hard for you to say exactly what 0:08:43.040 --> 0:08:47.920 the structure of that that that pathway. So you have 0:08:48.000 --> 0:08:50.600 to do X rays of these things, and then you 0:08:50.600 --> 0:08:54.040 have to very carefully analyze it and understand which parts 0:08:54.040 --> 0:08:57.400 are folded over, which other parts are behind, or they 0:08:57.440 --> 0:09:00.840 loop around, And it takes a huge amount of time 0:09:01.160 --> 0:09:03.560 and a lot of money just to do one, which 0:09:03.600 --> 0:09:06.800 is why it's not considered an efficient way of figuring 0:09:06.840 --> 0:09:09.920 this out. So um, however, you know, there are some 0:09:10.040 --> 0:09:13.240 educated guesses that we can make about the way that 0:09:13.280 --> 0:09:15.480 this sort of thing happens based on a bunch of 0:09:15.480 --> 0:09:18.120 different factors, and you know, these wonderful things that we 0:09:18.160 --> 0:09:21.520 have these days called computers to make that a lot easier. 0:09:21.559 --> 0:09:24.080 You know, once you once you code an algorithm of 0:09:24.480 --> 0:09:26.480 you know, trying to figure out how something like this 0:09:26.600 --> 0:09:30.000 might function. A computer can solve for a bunch of 0:09:30.040 --> 0:09:33.240 possibilities of how it's going to turn out. And so 0:09:33.880 --> 0:09:36.800 this work started way back in the nineteen sixties, not 0:09:36.880 --> 0:09:39.360 necessarily with computers at this point, but just learning about 0:09:39.400 --> 0:09:41.920 the importance of folding. This is when we started to 0:09:41.920 --> 0:09:44.800 really learn about the shapes of proteins. And there was 0:09:44.800 --> 0:09:46.679 a research team that was led by a felon in 0:09:46.800 --> 0:09:50.960 christian Anfinson who experimented with a protein and found that 0:09:51.120 --> 0:09:54.480 denaturing it, which meant that he added certain chemicals and 0:09:54.559 --> 0:09:58.920 heated the protein, would end up making it inert useless. 0:09:58.960 --> 0:10:02.679 It ended up unful holding and became unable to do 0:10:02.760 --> 0:10:05.360 what it was meant to do. Then he found out 0:10:05.400 --> 0:10:08.080 that if he removed those chemicals and lowered the temperature 0:10:08.080 --> 0:10:10.640 of the protein again, it would start to fold in 0:10:10.720 --> 0:10:13.560 on itself and regain the shape that it had when 0:10:13.559 --> 0:10:16.559 it started, which began to suggest, hey, the shape is 0:10:16.559 --> 0:10:20.600 actually important. It's not some random massive folding here. There's 0:10:20.640 --> 0:10:24.880 something more going on. And uh Infanson would eventually win 0:10:24.920 --> 0:10:28.400 a Nobel Prize for that work. So how do you 0:10:28.480 --> 0:10:30.679 know what shape is the right one? I mean, how 0:10:30.800 --> 0:10:34.480 how does a protein quote unquote no, I mean obviously 0:10:34.480 --> 0:10:37.600 the protein can't know. It doesn't have any way of thinking, 0:10:37.679 --> 0:10:40.280 not that we're personally aware of. That protein could have 0:10:40.280 --> 0:10:42.640 a really complex life. You don't know it's life. I mean, 0:10:42.840 --> 0:10:45.200 I don't mean to judge, all right, I admit, I mean, 0:10:45.679 --> 0:10:48.120 based upon what I understand, there's no way for a 0:10:48.160 --> 0:10:50.520 protein to know what shape it's supposed to be. So 0:10:51.200 --> 0:10:53.440 there and like we said, there are tons of different 0:10:53.480 --> 0:10:57.080 ways of protein could fold into any particular shape. Uh 0:10:57.120 --> 0:11:00.880 A fell by the name of Cyrus Levinthal actually calculated 0:11:00.880 --> 0:11:03.400 that if you took a protein of a hundred amino acids, 0:11:03.440 --> 0:11:05.920 remember that would be a short protein, all right. If 0:11:05.960 --> 0:11:08.520 you took a hunt protein that was a hundred mino acids, 0:11:08.559 --> 0:11:11.600 and you assumed that it could only have two different 0:11:11.640 --> 0:11:16.120 spatial orientations between any two amino acids, so links one 0:11:16.160 --> 0:11:18.520 and two could have one of two different than two 0:11:18.559 --> 0:11:21.680 and three, etcetera, etcetera. When you add that up across 0:11:21.800 --> 0:11:24.720 all one amino acids, you end up with ten to 0:11:24.760 --> 0:11:28.520 the power of thirty different shaps. So yeah, put thirty 0:11:28.600 --> 0:11:31.959 zeros behind that ten and there that's how many possible 0:11:32.080 --> 0:11:34.679 shapes there are. So how do you how how is 0:11:34.720 --> 0:11:37.400 it that a protein something that as like I said, 0:11:37.440 --> 0:11:40.480 as far as I know, unless there's some weird metaphysical 0:11:40.480 --> 0:11:43.640 thing going on, I can't make this determination itself. How 0:11:43.720 --> 0:11:46.320 is it that that this has happened? You know, it 0:11:46.320 --> 0:11:48.200 seems like it would be impossible for it to happen 0:11:48.280 --> 0:11:53.360 just accidentally. Here's the rub we're talking about folding. Folding 0:11:53.440 --> 0:11:58.559 is an action, and an action requires something very specific. Energy. Yes, 0:11:59.400 --> 0:12:02.800 you have to have energy to make this happen. Now, 0:12:02.840 --> 0:12:07.120 in nature, we tend to see things evolved to a 0:12:07.160 --> 0:12:09.600 point where they are able to do what they need 0:12:09.640 --> 0:12:12.000 to do with the least amount of energy needed to 0:12:12.040 --> 0:12:14.760 do it. Right, the path of least resistance is usually 0:12:14.880 --> 0:12:19.040 what wins out evolutionarily speaking. Right. So, so when you 0:12:19.080 --> 0:12:21.280 think of it that way, if you think, well, it 0:12:21.360 --> 0:12:23.720 makes sense for this to happen in a way where 0:12:23.760 --> 0:12:26.760 it's going to require the least amount of energy for 0:12:26.800 --> 0:12:29.800 it to happen, then you realize that the reason that's 0:12:29.800 --> 0:12:33.040 folding in this way is because each individual fold is 0:12:33.559 --> 0:12:37.360 more often than not, the most energy efficient fold for 0:12:37.400 --> 0:12:41.800 that particular pair of amino acids. So once you know 0:12:41.920 --> 0:12:44.800 that and you're able to build those rules into. Say 0:12:44.920 --> 0:12:47.839 I don't know a computer algorithm, and you say, when 0:12:47.880 --> 0:12:52.320 it's whenever you have these two amino acids uh next 0:12:52.360 --> 0:12:54.760 to each other, they are going to fold in this 0:12:54.840 --> 0:12:58.480 particular way, or or the rules of how these amino 0:12:58.520 --> 0:13:01.079 acids are close to one another will mean that they 0:13:01.080 --> 0:13:04.520 will either attract or repel or whatever, because it all 0:13:04.520 --> 0:13:07.480 depends upon the amino acids. Then you start building that in, 0:13:07.600 --> 0:13:09.320 and it has to get more and more complex, right 0:13:09.320 --> 0:13:11.560 because as they get longer. If you have a fold 0:13:11.720 --> 0:13:15.400 coming in on itself and two amino acids are pushing apart, 0:13:15.840 --> 0:13:17.640 then you know they're only going to get so close 0:13:17.679 --> 0:13:19.800 before it starts folding a different way. You have to 0:13:19.800 --> 0:13:22.319 build in all those rules, which is going to take 0:13:22.360 --> 0:13:25.720 a lot of time. And then you take your string 0:13:25.720 --> 0:13:29.280 of amino acids and say, according to these rules, find 0:13:29.679 --> 0:13:35.959 the configuration that overall will be the least uh energy. Uh, 0:13:36.200 --> 0:13:39.280 it will consume the least amount of energy. Now, even 0:13:39.480 --> 0:13:43.480 knowing all those rules and being able to say, program 0:13:43.480 --> 0:13:47.400 a computer to understand them exactly understand, Yeah, those were 0:13:47.440 --> 0:13:50.760 air quotes that you didn't hear. Um. Yeah, even even 0:13:50.800 --> 0:13:54.880 to follow all that using a normal computer to analyze 0:13:54.960 --> 0:13:57.560 all potential folds to find the final form would take 0:13:57.600 --> 0:14:00.880 a while. So, for example, fifty all the seconds of 0:14:01.040 --> 0:14:04.800 protein folding would take about thirty thousand years for your 0:14:04.840 --> 0:14:08.679 typical computer to analyze. Well, it's it's a really advanced 0:14:08.800 --> 0:14:12.480 version of that traveling salesman problem that classical computers have 0:14:12.559 --> 0:14:15.480 such a problem with. Right. The class the traveling salesman problem, 0:14:15.520 --> 0:14:17.240 if you're not familiar with it, is the idea that 0:14:17.280 --> 0:14:21.520 you're a traveling salesman and there are fifteen different cities 0:14:21.560 --> 0:14:23.960 that you need to visit, and you want to find 0:14:24.120 --> 0:14:28.160 the most efficient route to visit all of those fifteen cities. 0:14:28.280 --> 0:14:31.000 You can cross back over your own path. That's fine, 0:14:31.520 --> 0:14:33.160 so you don't have to you know, you don't have 0:14:33.200 --> 0:14:35.400 to ever make sure you don't cross over something. But 0:14:35.440 --> 0:14:37.240 you still have to find the most efficient one. And 0:14:37.280 --> 0:14:40.119 every time you add another city, the problem becomes more complex, 0:14:40.320 --> 0:14:43.840 and that's what classical computers are not so great at. Now, 0:14:43.880 --> 0:14:47.040 one thing you can do is add more processing cores 0:14:47.280 --> 0:14:49.880 and create a multi threaded approach, and that's the same 0:14:49.880 --> 0:14:53.440 thing that we see in protein folding. Right. For a while, 0:14:53.760 --> 0:14:57.720 distributed computing was a really big thing in this research. Exactly, 0:14:57.760 --> 0:15:00.640 and distributed computing is what it sounds like. We end 0:15:00.720 --> 0:15:03.440 up using lots of different computers to work on the 0:15:03.480 --> 0:15:07.520 same problem simultaneously. They're usually linked together at least, if 0:15:07.520 --> 0:15:10.280 not together with each other, they're linked to a central 0:15:10.680 --> 0:15:13.680 kind of administrative computer. Their networked in one way or another. 0:15:13.680 --> 0:15:15.520 It doesn't need to be like a like a local area. 0:15:15.600 --> 0:15:17.320 It doesn't have to be peer to peer or anything 0:15:17.360 --> 0:15:19.280 like that. It can be, it doesn't have to be. 0:15:19.680 --> 0:15:23.560 And so we started seeing some approaches to using this 0:15:23.680 --> 0:15:28.880 model to make it more efficient to simulate protein folding 0:15:28.920 --> 0:15:32.080 to find the shapes that it would most likely take. 0:15:32.400 --> 0:15:35.200 Keep in mind that in these situations where you have 0:15:35.240 --> 0:15:39.320 a computer making these calculations, the answer we ultimately get 0:15:39.840 --> 0:15:43.600 is is still kind of best guess, right. It's like 0:15:43.720 --> 0:15:47.200 it has a certain probability of being the right answer, well, 0:15:47.240 --> 0:15:49.880 you know, once you solve for that best guess than 0:15:50.200 --> 0:15:54.800 someone who knows stuff, you know, and actual scientists probably 0:15:54.920 --> 0:15:57.320 can look at that and go through the entire thing 0:15:57.480 --> 0:16:02.040 and and make a pretty educated reason whether or not 0:16:02.160 --> 0:16:06.200 it's whether or not it's accurate exactly. And this means 0:16:06.240 --> 0:16:10.360 that not only can we see the potential for figuring 0:16:10.360 --> 0:16:14.760 out how current proteins are folding, but perhaps even make 0:16:14.920 --> 0:16:19.240 new synthetic proteins that, based upon their sequence and shape, 0:16:19.640 --> 0:16:23.560 do very specific things. We'll talk more about that in Yeah. So, 0:16:25.120 --> 0:16:29.200 the most famous version of this distributed computing approach that 0:16:29.280 --> 0:16:31.280 I know of, I mean, there may be others, but 0:16:31.640 --> 0:16:35.360 is the the folding at home program that's usually known 0:16:35.400 --> 0:16:39.880 as folding at symbol home. It's from Stanford that came 0:16:39.960 --> 0:16:43.640 up with this. I mean people at Stanford did not 0:16:43.640 --> 0:16:46.680 not the institution like like a protein. As far as 0:16:46.760 --> 0:16:49.760 I know, Stanford, the Institution of Stanford does not have 0:16:49.840 --> 0:16:52.840 its own ability to think. But yeah, the way, now 0:16:53.000 --> 0:16:55.120 that's I'm more suspicious about that than I was about 0:16:55.120 --> 0:16:57.800 the Now you're talking about like a group intelligence arising 0:16:57.840 --> 0:17:00.920 from all right, well, okay, that's a plosophical argument we 0:17:00.960 --> 0:17:03.680 can have for another show. But yeah, the the the 0:17:03.840 --> 0:17:06.240 idea here was that you could, and you still can, 0:17:06.320 --> 0:17:09.399 by the way, download a program that you install on 0:17:09.440 --> 0:17:11.840 your computer. It runs in the background and it uses 0:17:11.880 --> 0:17:15.840 your your free processing space to help solve equations. Exactly 0:17:16.119 --> 0:17:19.320 what it does is it divides up these huge protein 0:17:19.400 --> 0:17:23.600 folding problems into individual work units. A work unit is 0:17:23.640 --> 0:17:27.840 just a section of that protein, where your your computer 0:17:27.920 --> 0:17:31.919 is essentially going through all the different possible combinations of 0:17:31.960 --> 0:17:34.359 folds to figure out which one seems to be the 0:17:34.359 --> 0:17:36.800 most efficient. Then once your computer has done with that, 0:17:36.920 --> 0:17:40.480 it sends that result back to the main computers at Stanford, 0:17:40.760 --> 0:17:43.800 which then uh compile them and yeah, and then it's 0:17:43.840 --> 0:17:46.199 kind of like putting a puzzle together. It puts all 0:17:46.200 --> 0:17:49.439 those individual work units together and they then have to 0:17:49.480 --> 0:17:52.719 see if that in fact makes sense. But yeah, it's 0:17:52.720 --> 0:17:54.919 one of those things that if one computer were doing this, 0:17:55.080 --> 0:17:57.439 it would take thousands of years. But but but dividing it 0:17:57.520 --> 0:18:01.720 up it takes much less time. It's pretty neat. It 0:18:01.800 --> 0:18:05.480 also has a screen saver element to it, so you 0:18:05.560 --> 0:18:09.280 get these kind of cool representations of what your section 0:18:09.320 --> 0:18:12.359 of the protein looks like with the various folds. Um, 0:18:12.760 --> 0:18:16.960 but it's a screen saver, so it's passive. But what 0:18:17.160 --> 0:18:20.560 if there were a way to make it not a 0:18:20.600 --> 0:18:24.320 passive experience but an active one. What if well, as 0:18:24.359 --> 0:18:27.680 it turns out, and as everyone listening to this probably 0:18:27.680 --> 0:18:30.640 knows at the very least from our introduction, um, if 0:18:30.680 --> 0:18:34.200 not from the internet, Uh, this is a real thing 0:18:34.280 --> 0:18:37.960 that there are in fact active ways that a normal 0:18:37.960 --> 0:18:40.160 old computer user at home who does not have any 0:18:40.240 --> 0:18:44.879 kind of degrees in bioengineering can participate in this process. 0:18:45.000 --> 0:18:48.840 And what gamers may in fact, well gamers not may, 0:18:49.000 --> 0:18:53.080 but are in some cases provably better at computers than 0:18:53.160 --> 0:18:59.440 doing this work. But we just we just established that 0:18:59.760 --> 0:19:06.040 these proteins have potentially millions of different different configurations. I 0:19:06.119 --> 0:19:08.560 just don't get it all right, let me lay some 0:19:08.680 --> 0:19:12.280 groundwork here so we can finally understand how playing a 0:19:12.359 --> 0:19:18.000 video game can solve this protein folding problem. So there's 0:19:18.040 --> 0:19:21.240 a particular game called fold It right now. The people 0:19:21.280 --> 0:19:25.000 behind Folded include a fellow named David Baker, who's a 0:19:25.040 --> 0:19:29.560 biochemistry professor at the University of Washington, and he liked 0:19:29.640 --> 0:19:33.120 to compete still does in the Critical Assessment of Techniques 0:19:33.160 --> 0:19:36.439 for Protein Structure Prediction also known as CASP, which is 0:19:36.480 --> 0:19:40.800 a competition and protein folding predictions. UH. Usually you end 0:19:40.880 --> 0:19:44.560 up having certain difficult problems handed out to the participants, 0:19:44.600 --> 0:19:47.439 who all then do their best to try and figure 0:19:47.440 --> 0:19:50.440 out the way that the protein actually folds. You submit 0:19:50.480 --> 0:19:53.040 that to a panel of experts who then look and 0:19:53.080 --> 0:19:56.280 see which one got it closest to what is reality, 0:19:56.720 --> 0:19:59.520 and then their awarded a prize. Now, David Baker had 0:19:59.520 --> 0:20:03.080 been used being something called Rosetta at Home, very similar 0:20:03.160 --> 0:20:05.800 to folding at home. It was a distributed computer network 0:20:05.840 --> 0:20:10.280 still is um developed so that a lot of computers 0:20:10.280 --> 0:20:11.880 could work on the same problem at the same time. 0:20:11.920 --> 0:20:14.480 It was the equivalent back in two thousand six of 0:20:14.520 --> 0:20:18.320 a seventies seven Terra Flop supercomputer, so gave him a 0:20:18.320 --> 0:20:20.560 little bit of an advantage in the competition. Yeah, you know, 0:20:20.640 --> 0:20:24.840 not everyone has access to either a distributed network or 0:20:24.920 --> 0:20:28.879 a supercomputer, so it certainly was helpful. However, he was 0:20:28.920 --> 0:20:31.879 still finding that there were some protein folding problems that 0:20:31.920 --> 0:20:36.600 were difficult even using this incredibly sophisticated tool. So what 0:20:36.600 --> 0:20:39.520 what to do. Well, a mutual friend of his and 0:20:39.600 --> 0:20:44.960 another person named Zoran Popovic or Popovich perhaps, um I 0:20:45.000 --> 0:20:49.520 apologize Zorin, I I'm mispronouncing your name. Anyway, the two 0:20:49.560 --> 0:20:52.920 of them teamed up. Now, Popovich was a computer scientist 0:20:53.040 --> 0:20:57.320 at the University of Washington, interested in graphical design as 0:20:57.320 --> 0:21:00.600 well as sort of looking at the human ability to 0:21:00.680 --> 0:21:04.239 puzzle things out in an intuitive way that computers just 0:21:04.440 --> 0:21:07.080 can't do. As we have talked about. Well, not related 0:21:07.119 --> 0:21:11.480 to Zorin specifically, but the brain's ability to parse out 0:21:11.560 --> 0:21:14.880 certain problems versus that of a classical computer. We've talked 0:21:14.880 --> 0:21:18.240 about that a bunch of around our sister show Forward Thinking. Yeah, 0:21:18.280 --> 0:21:20.520 so um, we will try to link that out on 0:21:20.560 --> 0:21:23.000 social if it's a topic that you're specifically interested in. 0:21:23.280 --> 0:21:26.680 But yet together they came up with this idea for Folded. Yeah, 0:21:26.680 --> 0:21:29.679 it's really cool. The game's physics are based on the 0:21:29.720 --> 0:21:32.600 real world physics we were talking about that computer algorithms 0:21:32.680 --> 0:21:35.320 rely upon for when they're, you know, doing the simulated 0:21:35.400 --> 0:21:38.760 protein folding and they're looking for that most efficient shape. 0:21:39.160 --> 0:21:42.760 So the rules of what shapes can be made adhere 0:21:42.800 --> 0:21:44.719 to the real world rules that you would find if 0:21:44.720 --> 0:21:48.440 you were to look at that molecular scale. Now, players 0:21:48.480 --> 0:21:51.080 are essentially presented with what looks to be like a 0:21:51.080 --> 0:21:54.440 giant tangle of knots um, and then they are able 0:21:54.480 --> 0:21:58.520 to manipulate this giant tangle in various ways, and they 0:21:58.600 --> 0:22:01.080 will see they have a score, and their score goes 0:22:01.240 --> 0:22:05.440 up as they find the configurations that most uh fit 0:22:05.760 --> 0:22:09.399 the efficient model of what that protein would be. So 0:22:09.800 --> 0:22:12.360 you use your score to kind of guide you, and 0:22:12.440 --> 0:22:14.399 you can do all sorts of things. You can pull 0:22:14.520 --> 0:22:18.080 you can push, you can jiggle. Uh, there are all 0:22:18.080 --> 0:22:20.480 these different things you can do with essentially your mouse 0:22:20.880 --> 0:22:24.440 to move these amino acid blocks around and find out 0:22:24.480 --> 0:22:30.200 which shape is the the most ideal. And there's actually uh, Lauren, 0:22:30.280 --> 0:22:34.080 you found a really good article about this, uh that 0:22:34.080 --> 0:22:37.800 that was really entertaining and told a whole story about this. 0:22:37.840 --> 0:22:40.159 I believe it was in Wired, and it was so 0:22:40.240 --> 0:22:43.800 exciting to read the story because it added the drama. 0:22:43.880 --> 0:22:47.320