Folding the Proteins

can do that thing? We can and we did well well, I mean yes, we did. The research is in the past, the podcasting is in the immediate future. Yes, yes, has houses going to We're going to now podcast about the thing we've been researching. We're kind of delaying because, as it turns out, there's there's quite a bit of groundwork we have delay before we can get into the technology because just saying what the technology does doesn't really do

it justice. You don't understand how complex the problem is until you understand the basics about proteins themselves. Right, Um, So let's talk first about what protein folding is and why it's so important because okay, so and this does have to do with technology, not not just the algorithm part, but biological technology. We're we're talking here about cellular programming,

not like cell phone programming, but biological cells. Yes, Um, the software that tells living cells what to do are proteins. And proteins are strings or chains made up of different amino acids, depending on a bunch of different factors, like the structure of each amino acid in the chain, that the order of the amino acids in the chain, and

the presence of little genetic bits that act like stop signals. Um, these chains come together and then fold up into these really complex three dimensional shapes, and once they're in those shapes, they can form structures or act as chemical catalysts to set off any of the functions of a cell. That they're directly responsible for life happening basically, so, so doctors

and scientists are pretty interested in how they form. And you may be asking, all right, so what exactly I mean, you're giving me kind of a big picture, but what exactly are they responsible for? So here are just a few examples. Keep in mind this is not an exhaustive list, certainly not so supporting the skeleton that's a big deal for us. I mean we don't want to just be blobs of people. I mean sometimes I do, but sometimes downhill to just melt under my desk, That's true. There

are there are those days. Then there's a there's controlling our senses. That's important. Obviously moving muscles. So even if you didn't have that skeleton, presumably you'd want to have some say over where you were going. I would. Yeah, Digesting food very important, that's actually my primary Yeah, I dedicate nearly seven percent of all brain power into figuring out where I'm going to get my food next. Then defending against infections very important to process emotions. So here's

what it boils down to. If it's a biological function, you can bet proteins are involved in it in some fashion, and usually they're ultimately responsible for what's going on now. In nature, the way that a protein forms is through this process of linking together the appropriate amino acids. Right, these twenty different building blocks that can make up all these different types of proteins, and the sequence will determine

what the function of the protein is. But the protein itself will not be functional until it's in its final shape, which is called the tertiary structure, so called because the protein folds into a secondary structure first, uh, and that's just a pretty simple one, one of a couple of different different possibilities before settling into its final three dimensional form. And then once you've got that three dimensional form, that's

when the protein can do what it is supposed to do. Now, remember I said there were just twenty different amino acids, So those are your twenty basic building blocks. Now, so far we've identified more than a hundred thousand different proteins that are in human bodies alone, all made from those building blocks. Yeah, so it just means that all the different combinations. Some some of these proteins are relatively short, meaning that they might be a hundred or so amino

acid blocks long. Some of them can be more than a thousand blocks long. So that means that, uh, it gets pretty complicated just based upon the sequence of amino acids. Then you have to think of the possible orientations those blocks can have in relation to each other during this whole folding process. Sure, and also I wanted to put in that protein misfolding, which can be caused by a

number of factors as well. It is thought to cause health problems from allergies, to diseases likes to fibrosis, to most degenerative brain diseases like Alzheimer's, and this is all due to to flawed protein structures giving bad instructions to cells. Right, So what we're getting at here is that this is this is pretty complicated, right. Yeah. The shapes of these protein structures are incredibly difficult to predict because the language

that they're coded in is really whibbly wobbly. The same way that you can say something in a lot of different ways in English, or you know, get a desired effect in photoshop through a lot of different options, or solve an equation through different methods, genetic code is redundant. The same amino acid can be built from different building blocks, and it's it's not it's not all a one to one ratio of it's not a it's not a one

to one factor of how something's going to work. Right. Yeah, you can't easily predict just based upon like if I gave you a sequence of amino acids that made up a protein, you could not automatically say, oh, this is exactly how it's going to fauld because, like we were saying, there are lots, Yeah, there are a lot of potential

ways that this can happen. Some of the shapes that you can encounter with proteins include round proteins that's like hemoglobin, long proteins collagen would be an example, strong proteins, which includes spectron that protects the cells that carry oxygen from our lungs to everywhere else it needs to go. Or elastic proteins like titan, which controls muscle stretching and contraction. And here's another fun fact. The chemical name for Titan

is more than one hundred eighty nine thousand letters long. Yeah, it takes three and a half hours to pronounce the full chemical name for titan. I am not making this up three and a half hours, So here we go. No, I'm just kidding. We we've never done a three and a half hour long podcast. We will not be doing one today. But it is the largest protein we've identified so far, so I guess it it's entitled to a

three and a half hour long name. There are, by the way, videos on YouTube that you can watch that have the full pronunciation three and a half hours. I'm glad that someone else has done that so that we don't have to. Yeah, it will try to link that out on social just in case you're curious. The one I watched was obviously a Russian person pronouncing it, because the the annunciation was very Russian. But he started off already looking pensive and bored before. I don't know if

it was staged to like what he had. He had a nice little vase of flowers next to him, and I mean it was I didn't. I didn't watch all three and a half hours, so I don't know how much of it changed. I did see someone point out that there was a apparently an obvious cut in the video some two hours in. Give the guy a break, literally, give the guy a break, alright. So the sequence of amino acids makes it really easy to predict what the secondary structure of the protein will look like. That that

intermediary step and that part is easy to predict. But what the fine old tertiary structure will be like is a totally different problem. And to learn that we have to do lots of experiments, and according to Nature dot com, we only have data on ten of all the proteins we've identified where we can reasonably say the way that they fold. Part of that is because you might say, well, Why don't we just look at the protein. Why don't we just look at it, then we can see how

it folds where's the problem? It actually is an incredibly long process because these proteins are are made up of the very tiny components and they fold in on themselves. Right, So imagine that you just came up to a mass of string and it's all knotted up in a big wad. It'd be really hard for you to say exactly what

the structure of that that that pathway. So you have to do X rays of these things, and then you have to very carefully analyze it and understand which parts are folded over, which other parts are behind, or they loop around, And it takes a huge amount of time and a lot of money just to do one, which is why it's not considered an efficient way of figuring

this out. So um, however, you know, there are some educated guesses that we can make about the way that this sort of thing happens based on a bunch of different factors, and you know, these wonderful things that we have these days called computers to make that a lot easier. You know, once you once you code an algorithm of you know, trying to figure out how something like this might function. A computer can solve for a bunch of

possibilities of how it's going to turn out. And so this work started way back in the nineteen sixties, not necessarily with computers at this point, but just learning about the importance of folding. This is when we started to

really learn about the shapes of proteins. And there was a research team that was led by a felon in christian Anfinson who experimented with a protein and found that denaturing it, which meant that he added certain chemicals and heated the protein, would end up making it inert useless. It ended up unful holding and became unable to do

what it was meant to do. Then he found out that if he removed those chemicals and lowered the temperature of the protein again, it would start to fold in on itself and regain the shape that it had when it started, which began to suggest, hey, the shape is actually important. It's not some random massive folding here. There's something more going on. And uh Infanson would eventually win a Nobel Prize for that work. So how do you

know what shape is the right one? I mean, how how does a protein quote unquote no, I mean obviously the protein can't know. It doesn't have any way of thinking, not that we're personally aware of. That protein could have a really complex life. You don't know it's life. I mean, I don't mean to judge, all right, I admit, I mean, based upon what I understand, there's no way for a protein to know what shape it's supposed to be. So there and like we said, there are tons of different

ways of protein could fold into any particular shape. Uh A fell by the name of Cyrus Levinthal actually calculated that if you took a protein of a hundred amino acids, remember that would be a short protein, all right. If you took a hunt protein that was a hundred mino acids, and you assumed that it could only have two different spatial orientations between any two amino acids, so links one and two could have one of two different than two

and three, etcetera, etcetera. When you add that up across all one amino acids, you end up with ten to the power of thirty different shaps. So yeah, put thirty zeros behind that ten and there that's how many possible shapes there are. So how do you how how is it that a protein something that as like I said, as far as I know, unless there's some weird metaphysical thing going on, I can't make this determination itself. How

is it that that this has happened? You know, it seems like it would be impossible for it to happen just accidentally. Here's the rub we're talking about folding. Folding is an action, and an action requires something very specific. Energy. Yes, you have to have energy to make this happen. Now, in nature, we tend to see things evolved to a point where they are able to do what they need to do with the least amount of energy needed to do it. Right, the path of least resistance is usually

what wins out evolutionarily speaking. Right. So, so when you think of it that way, if you think, well, it makes sense for this to happen in a way where it's going to require the least amount of energy for it to happen, then you realize that the reason that's folding in this way is because each individual fold is more often than not, the most energy efficient fold for that particular pair of amino acids. So once you know

that and you're able to build those rules into. Say I don't know a computer algorithm, and you say, when it's whenever you have these two amino acids uh next to each other, they are going to fold in this particular way, or or the rules of how these amino acids are close to one another will mean that they will either attract or repel or whatever, because it all depends upon the amino acids. Then you start building that in, and it has to get more and more complex, right

because as they get longer. If you have a fold coming in on itself and two amino acids are pushing apart, then you know they're only going to get so close before it starts folding a different way. You have to build in all those rules, which is going to take a lot of time. And then you take your string of amino acids and say, according to these rules, find the configuration that overall will be the least uh energy. Uh,

it will consume the least amount of energy. Now, even knowing all those rules and being able to say, program a computer to understand them exactly understand, Yeah, those were air quotes that you didn't hear. Um. Yeah, even even to follow all that using a normal computer to analyze all potential folds to find the final form would take a while. So, for example, fifty all the seconds of protein folding would take about thirty thousand years for your

typical computer to analyze. Well, it's it's a really advanced version of that traveling salesman problem that classical computers have such a problem with. Right. The class the traveling salesman problem, if you're not familiar with it, is the idea that you're a traveling salesman and there are fifteen different cities that you need to visit, and you want to find the most efficient route to visit all of those fifteen cities.

You can cross back over your own path. That's fine, so you don't have to you know, you don't have to ever make sure you don't cross over something. But you still have to find the most efficient one. And every time you add another city, the problem becomes more complex, and that's what classical computers are not so great at. Now, one thing you can do is add more processing cores and create a multi threaded approach, and that's the same thing that we see in protein folding. Right. For a while,

distributed computing was a really big thing in this research. Exactly, and distributed computing is what it sounds like. We end up using lots of different computers to work on the same problem simultaneously. They're usually linked together at least, if not together with each other, they're linked to a central kind of administrative computer. Their networked in one way or another. It doesn't need to be like a like a local area. It doesn't have to be peer to peer or anything

like that. It can be, it doesn't have to be. And so we started seeing some approaches to using this model to make it more efficient to simulate protein folding to find the shapes that it would most likely take. Keep in mind that in these situations where you have a computer making these calculations, the answer we ultimately get

is is still kind of best guess, right. It's like it has a certain probability of being the right answer, well, you know, once you solve for that best guess than someone who knows stuff, you know, and actual scientists probably can look at that and go through the entire thing and and make a pretty educated reason whether or not

it's whether or not it's accurate exactly. And this means that not only can we see the potential for figuring out how current proteins are folding, but perhaps even make new synthetic proteins that, based upon their sequence and shape, do very specific things. We'll talk more about that in Yeah. So, the most famous version of this distributed computing approach that I know of, I mean, there may be others, but is the the folding at home program that's usually known

as folding at symbol home. It's from Stanford that came up with this. I mean people at Stanford did not not the institution like like a protein. As far as I know, Stanford, the Institution of Stanford does not have its own ability to think. But yeah, the way, now that's I'm more suspicious about that than I was about the Now you're talking about like a group intelligence arising from all right, well, okay, that's a plosophical argument we

can have for another show. But yeah, the the the idea here was that you could, and you still can, by the way, download a program that you install on your computer. It runs in the background and it uses your your free processing space to help solve equations. Exactly what it does is it divides up these huge protein

folding problems into individual work units. A work unit is just a section of that protein, where your your computer is essentially going through all the different possible combinations of folds to figure out which one seems to be the most efficient. Then once your computer has done with that, it sends that result back to the main computers at Stanford, which then uh compile them and yeah, and then it's

kind of like putting a puzzle together. It puts all those individual work units together and they then have to see if that in fact makes sense. But yeah, it's one of those things that if one computer were doing this, it would take thousands of years. But but but dividing it up it takes much less time. It's pretty neat. It also has a screen saver element to it, so you get these kind of cool representations of what your section of the protein looks like with the various folds. Um,

but it's a screen saver, so it's passive. But what if there were a way to make it not a passive experience but an active one. What if well, as it turns out, and as everyone listening to this probably knows at the very least from our introduction, um, if not from the internet, Uh, this is a real thing that there are in fact active ways that a normal old computer user at home who does not have any kind of degrees in bioengineering can participate in this process.

And what gamers may in fact, well gamers not may, but are in some cases provably better at computers than doing this work. But we just we just established that these proteins have potentially millions of different different configurations. I just don't get it all right, let me lay some groundwork here so we can finally understand how playing a video game can solve this protein folding problem. So there's

a particular game called fold It right now. The people behind Folded include a fellow named David Baker, who's a biochemistry professor at the University of Washington, and he liked to compete still does in the Critical Assessment of Techniques for Protein Structure Prediction also known as CASP, which is a competition and protein folding predictions. UH. Usually you end up having certain difficult problems handed out to the participants, who all then do their best to try and figure

out the way that the protein actually folds. You submit that to a panel of experts who then look and see which one got it closest to what is reality, and then their awarded a prize. Now, David Baker had been used being something called Rosetta at Home, very similar to folding at home. It was a distributed computer network still is um developed so that a lot of computers could work on the same problem at the same time.

It was the equivalent back in two thousand six of a seventies seven Terra Flop supercomputer, so gave him a little bit of an advantage in the competition. Yeah, you know, not everyone has access to either a distributed network or a supercomputer, so it certainly was helpful. However, he was still finding that there were some protein folding problems that were difficult even using this incredibly sophisticated tool. So what

what to do. Well, a mutual friend of his and another person named Zoran Popovic or Popovich perhaps, um I apologize Zorin, I I'm mispronouncing your name. Anyway, the two of them teamed up. Now, Popovich was a computer scientist at the University of Washington, interested in graphical design as well as sort of looking at the human ability to puzzle things out in an intuitive way that computers just

can't do. As we have talked about. Well, not related to Zorin specifically, but the brain's ability to parse out certain problems versus that of a classical computer. We've talked about that a bunch of around our sister show Forward Thinking. Yeah, so um, we will try to link that out on social if it's a topic that you're specifically interested in. But yet together they came up with this idea for Folded. Yeah,

it's really cool. The game's physics are based on the real world physics we were talking about that computer algorithms rely upon for when they're, you know, doing the simulated protein folding and they're looking for that most efficient shape. So the rules of what shapes can be made adhere to the real world rules that you would find if

you were to look at that molecular scale. Now, players are essentially presented with what looks to be like a giant tangle of knots um, and then they are able to manipulate this giant tangle in various ways, and they will see they have a score, and their score goes up as they find the configurations that most uh fit the efficient model of what that protein would be. So you use your score to kind of guide you, and you can do all sorts of things. You can pull

you can push, you can jiggle. Uh, there are all these different things you can do with essentially your mouse to move these amino acid blocks around and find out which shape is the the most ideal. And there's actually uh, Lauren, you found a really good article about this, uh that that was really entertaining and told a whole story about this. I believe it was in Wired, and it was so exciting to read the story because it added the drama.

It was two different teams that were competing using this game, and they were exciting for getting Every time they get a point, everyone would just totally freak out. And there's one point where a thirteen year old kid made a move that got twenty points, which because they were getting towards the very end of the deadline where almost all

the improvements that could be found had been found. And uh, you find out that there are lots of teams out there that take this really seriously, that they really compete. So uh, it's tapping into that that part of the human brain where it's not just that we're great at at figuring out puzzles, but that were motivated to compete against others. Oh yeah, and it can be a really collaborative effort as well. That the game lets you create

little bits of code that act like shortcuts. They're they're called recipes in the game, and players can work together to perfect these recipes, you know, sharing and modifying and combining their favorite strategies. And the whole goal was just to use that human ability to seek out solutions, test things out, and just kind of intuitively figure out the right kind of shapes like that. Once you start to

recognize things, it's pattern development. Yeah, So again, instead of going through one at a time like a computer would, you might, well, for one thing, you might jump around a little bit. If one section doesn't seem to be giving you any more points, you might think, all right, well,

let's turn this around. Let's see if we can peer deeper into this tangle, and maybe there's something at the very core that we need to gently change, keeping in mind that sometimes a change can result in a dramatic kind of domino effect out through the rest of the structure. Of course, you can undo move so you don't have to worry about excidentally hitting hitting a button at just only all inferrals and you lose all your progress. It's not quite that bad. So the question is using this approach,

how well does it work? Really well? As it turns out, in research team including the creators have Folded, set up a test to see how their players were doing and found that given ten example proteins, folded players beat computer programs at coming to the best possible conclusion of the time, players tied with algorithms of the time, and the agorhythms

one just of the time. Another study in compared two recipes that have been developed by the folded player population that had become really popular alongside an algorithm that had been developed independently by professional genetic scientists, and they were really similar. So not only do we have an example of video gamers being able to work out some some puzzles, they're able to do it sometimes better than some of the most sophisticated computer or at least as well as

some of the most sophisticated computer algorithms out there. And they can also do it as well as people who know what they're talking about. Does pretty neat. I mean again, it's one of those things where if you if you put it in the form of a game, and you set up the rules in such a way that they are consistent, then folks can really shine. Someone with no knowledge of of genetic molecular structure can do it. And they don't necessarily gain a knowledge of how proteins fold.

They may not be able to express that in any way, but they're able to see again using that scoring Systemah. So back in then, folded players were able to unlock the structure of an enzyme that's related to AIDS. And this particular enzyme had been a real puzzle for for years.

It's part of the inner workings of a virus that causes autoimmune dysfunction in monkeys, and and a team, including people who have been working on sessing this structure out for more than ten years, challenged gamers to sess out the structure in three weeks. Unfair it took It took the gamers ten days. Face yeah, I mean it was

a huge breakthrough. Now, the Baker Lab, so named after David Baker, uh, chooses some of the folded solutions to synthesize proteins in the lab, and so there's an opportunity here to create synthetic proteins which could potentially be used in therapeutic treatments. Uh huh. Yeah. In the future, this kind of thing could be used to create better medicine. That is insane. I mean that what and why is

it able to create better messine? Well, going back to what we said at the very beginning, how proteins are the drivers for all biological function. They're also often the drivers of biological disfunction. So you may want to be able to figure out how to deliver medicine or drugs that would be effective in treating proteins that have been misfolded, like you had said earlier, Lauren. Or you may want to be able to quote unquote get rid of bad

proteins or or or lock them up somehow. For example, viruses, Yes, the HIV virus is made up mostly of proteins, So understanding that can help us learn new therapies to address, uh, you know, treating those sort of viruses or again to to limit how they can spread simply by creating you think of like a protein of virus. Protein is something that needs to bind in a certain way two cells. If we're able to uh to clog up those binding sites, then you render that virus in effective. Right, and think

about that. Okay, we could hypothetically create these proteins that would block viruses from causing any kind of large scale damage. This could be a cure for the flu or hepatitis, or herpes or rabies, or the cancer causing HPV human papaluma virus. Yeah, and speaking of cancer, it's uncontrolled cellular growth, right, that's the basic definition of cancer. Now, normally you have proteins like the P five three tumor suppressor that limits

cellular growth and prevent cancer from forming. They kind of have the the the off switch for that to happen. And frequently in cancer, that protein has been damaged in some way, right, which means that it is no longer able to govern that and as a result, that's when you start to see tumor growth. So it might be possible to learn ways to repair damaged P five three proteins to help prevent or treat cancer. So these are

these are big ideas that are really important. And it's not just in the medical field that we could see more deeper understanding proteins really pay off. Oh sure, biochemistry is a pretty huge thing. Oh yeah, it isn't just about health, although of course as a huge slice. Right,

But how about biofuels. So if you want to make a biofuel, you're talking about taking plants and then converting those plants into a fuel using some form of process, and that conversion process takes some time, and usually you're using some sort of microbial enzymes called cellulations, which are proteins.

There you go. So by studying proteins, by learning how they fold, and perhaps even creating synthetic proteins that can do the same job but do it better than the ones we already have, then you can make it more efficient to produce biofuels. If you make it more efficient, that means you can make more of it, and you can make it more exact, more cheap, more cheaper. I was gonna say cheaply, but that's fine cheaper. Yes. So this is why, or just two of the reasons why

studying proteins is so important. There are other reasons as well, and you know, we we can see lots of different potential um uses for for more for a deeper knowledge of how proteins work, and who knows, there's probably tons of stuff we can't even imagine right now that will become possible as we learn more about these very basic elements that make life possible. So really cool. Also, you go gamers really cow You know, I get excited if I managed to finally hit somebody with a sniper rifle

and Halo. And I'm not even talking with like shooting them. I mean actually doing a melee attack because I can't hit anything. So but they're here. We have gamers who are actually doing science, which is pretty neat. I'm actually I haven't had a chance to down load Folded yet to try it myself, but I'm going to do it. Yeah, I'm really excited about this. And this was so nice

to do this. It was a very heartwarming topic that that is just beautiful, has such terrific reach and and if you would like to be a part of that, folks, you can. It's free. You can just go to fold dot I t to get started. Yep, you can download that, or if you if you're not the gamer type and this doesn't sound interesting to you, you can always also download Folding at home and that will just run the background.

It will mean that your computer will do things a little slower than it normally does, not a lot, but it mostly is taking effect when you are not using your computer. So if you leave your computer on all the time, but you don't really you know, you only use it for a little bit of time that downtime could be dedicated to science. Yeah, so pretty cool stuff. All right. Well, this was a fun topic to go through. You know, it's a little bit more science heavy than

what we usually do, which was kind of fun. Uh. And we have to thank Caleb again for sending him the suggestion on Facebook. Guys, if you have any suggestions you would like to throw our way, there's some sort of technology that you want to hear more about, whether it is cutting edge or something that we developed ten years ago and haven't used since. Let us know, send

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