Ep 5 - The Genetic Code - Part 2

Life learned to speak in Episode 4. Now it’s time to speak clearly. Tina gets her anticodon. Rick becomes Darth Vader. The wobble gives evolution room to experiment. And LUCA emerges - the ancestor of all life on Earth.

Transcript

Jackie 0:02

Hello, I'm your host Jackie Mullins, and welcome to From Cells To Us, how the podcast where we figure out how life went from a single cell to complex creatures like us. Last episode, we learned to speak life went from cavemen, grunting to Babylonians, creating the first written laws. We watched RNA specialize into three types. TRNA, Tina, our designated driver, RRNA, Rick, the party house owner and MRNA, Mary, the one with the list. And together they invented a language, three letter words called coons. A UG means start, UA. A means stop. 64 combinations covering 20 amino acids. Amazing. But that early system was rough. It was like a toddler learning how to talk. Like sure they're making words now, but half of what comes outta their mouth is gibberish and good luck understanding what they actually want. I saw someone say on the internet, uh, a toddler is the closest you'll ever be to owning a Pokemon. It follows you around. You love it more than life. It listens only when it wants to, and only you can understand what it's saying. The main difference is training it to fight other toddlers is in fact frowned upon. So that's where this early system was at, you know, Pokemon slash toddler level. Life could speak, but life needed to speak clearly. Today we're talking about how the genetic code got refined, how sloppy translation became precise, how messy error prone system became so locked in, so universal that every living thing on earth, from bacteria to blue whales, to you as still using the exact same dictionary 3.5 billion years later also. We're still personifying the RNAs in this episode as well. So as a reminder, TRNA is Tina. Our RNA is Rick, and MRNA is our Mary. We're also going to finally explain some of the things I deliberately left out in episode four. Like what's actually going on with Tina when it matches a code on, and what happened when proteins joined the party at Rick's house. Let's get into it. Okay, so remember where we left off? The genetic code exists. Rick is reading Mary's list. It's calling for Tina. Tina brings the correct amino acid and Rick links the amino acids Tina brings together in the right order, which Mary brought over from DNA progress, but right order is generous. It's more like mostly right order or sometimes if you are lucky. Early translation was. like playing telephone at a loud party. The message starts out as bring the purple elephant, right? And by the end, someone's showing up with a purple cantaloupe. Close. Maybe useful, probably not. Okay, and a quick sidebar here. Maybe you're annoyed that I keep doing this. Keep hyping up some amazing feat, life accomplished, and then being like, and it was trash. And I get it. I do it every episode, but here's. The thing we're going from naked, barely formed, RNA strand to the complex incredible cells in your body right now. That's a long journey. So yeah, every step forward is amazing and still kind of garbage when you compare it to what comes next. It's like looking at an artist, early sketches. You ever see those side by side pictures of someone who's been learning for a few years? You see the first one and you're like, oh, wow, that's, that's amazing. And it is, but compared to what they'd paint later, you know, it's, it's rough, it's unrefined. They weren't bad. They just weren't done evolving yet. And that's where life is right now. Impressive. For its stage, but nowhere near the masterpiece it'll become, and that's evolution. It keeps getting better. So stick with me. So let's go back to the main event. Here's what was going wrong with the cell's. New language problem. One TRNA, mix up. Sometimes the wrong Tina would show up. I mean, come on Tina, get it together. Rick is calling for the one carrying methionine, but the one carrying Leucine pulls up instead. You know, oops, wrong amino acid in the chain. I. Problem two reading frame error. Remember Rick Reeds Mary three letters at a time? But what if it slips? What if Rick jumps the gun? He's just guzzled a five hour energy drink. He's ready to party. Mary's list comes in, and instead of reading it properly three letters at a time, he reads only the first letter and sends for Tina with like only an A and not a UG. She will not be coming with methionine. The whole message is now scrambled. Every single amino acid from that point on is wrong. It's like if someone accidentally hit the space bar in the wrong place and, uh, you know, the cat eight becomes the ccat e. Doesn't make any sense. Can't do that. Problem three mer degradation, RNA is fragile. Remember? Mary doesn't have protein support like Rick, so sometimes Mary would start falling apart while it was being read. Imagine trying to read a book while someone's ripping pages out of your hands. You know, it's not ideal. Problem four. No proofreading. This one's pretty self-explanatory. You know, there's no double checking. Whatever amino acids, Rick combined. There was no, Ugh. Like are we sure we got that right? No. Rick's still running on that five hour energy drink. Just connect, connect, connect. Get outta here. So proteins were being made. But they were full of errors. And a proteins function depends on its shape and its shape depends on its sequence. One wrong amino acid in the whole spot could mean the difference between a working enzyme and a useless blob. Life needed quality control. So let's tackle the first problem. How does the right Tina show up? Well, in episode four I told you that Rick reads the code on on Mary's list and calls for the matching Tina. But I didn't explain how Tina matches, like what makes the Tina carrying methionine respond to a UG and not anything else. The answer to that is the anticodon sounds menacing, right? Well, it's not. It's actually genius. Every Tina has two important ends. One end holds the amino acid. That's the cargo, that's her claw, so to speak. The other end has a three letter sequence called the Anticodon. That's her ID badge. Remember base pairing a pairs with UG pairs with C, you know, same thing here. If Mary's codon is a UG, then the matching, Tina has the anticodon of UACA pairs with UU pairs with a. GE pairs with C. They fit together like puzzle pieces. So when Rick reads a UG on Mary's list, it's not yelling out into the void. Hoping the right Tina shows up. The mRNA codon is literally sitting there exposed, waiting for a match, like a mini magnetic strip. Tina's float by and only the one with the complimentary anticodon can physically lock in. It's like a lock. And a key a UG from Mary is the lock. UAC from Tina is the key. Wrong key. It doesn't fit. It bounces right off, right key. It clicks into place. Rick grabs the amino acid and adds it to the chain. So to update our party analogy, Rick isn't really calling Tina on the phone anymore. It's more like Rick is holding up Mary's list at the door and each Tina has to show their ID badge, their anti-code on. And if your badge matches what's on the list you're in. If not, you bounced ya. Basic. The system is way more reliable than just hoping the right Tina wanders over the matching is built into the chemistry. Okay, so Tina's matching got better, but Rick was still struggling. Remember how I kept calling it the upgraded rib zyme or the party house? Well, that party house was about to get a serious renovation. College Rick was ready to grow up. Now here's what happened. More and more proteins started hanging around with Rick. He's a cool guy. We talked about this in episode four. Peptides wrapping around Rick, like a sprained ankle, holding it in the right shape. Well that kept happening. More peptides, longer. Peptides. Peptides that folded into specific shapes and did specific jobs. Some of these proteins helped Rick hold Mary in place. Hold the list down so it didn't float away or break apart, you know, no more Having pages ripped out from under Rick Mary is held steady so that Rick can read properly. Some helped position Tina correctly, making sure that ID badge or anti-codon lined up perfectly with Mary's coat on. Some helped Rick move along. Mary smoothly, three letters at a time. No skipping, no slipping. Some helped kick out the empty Tina's after its amino acid was taken out of its claw. This was no longer just an upgraded ribosome. This isn't just wrapping a sprained ankle anymore, not just holding a shape that works. This was Rick plus a whole crew of protein assistance all working together like a well-oiled machine. This was more like Darth Vader because the suit wasn't just keeping him together, right? It was breathing for him, it was helping him move his limbs, providing way more function than just stability Still. Obsidian black, of course, because you can't rule a death star in Robin's egg blue. So the proteins are helpers, but Rick is still the star. After 3.5 billion years, RNA is still doing the core work. So when I say ribosomes were important, I meant it. You've got ancient RNA chemistry happening inside you right now, and this is why I think starting from the beginning is a good idea. Alright, so we've got better matching with Tina's Anticodons. We've got a more stable ribosome with helper proteins, but. What about the errors that still slip through? Well, this is where things get clever. Now, remember I said there are 64 possible codons, but only 20 amino acids. That means multiple codons can code for the same amino acid. This is called redundancy. At first, that might seem wasteful, but redundancy is good. In this case, it's like knowing four different routes. Home, main road closed, take the side. Street construction on the highway. Well, there's a back way. They all get you to the same place home. This is the same with redundancy in the cell. I mean, leucine alone has four codons. That all start with cu U-C-U-U-C-U-C-C-U-A and CUG actually has six in total. But let's focus on these four. That's a built in error buffer. And here's why most the redundancy is in the third letter of the code on, see how the first two letters are always CU. Only the third letter changes, and they all mean leucine. So if there's a mutation in the third letter, or Rick's reading a codon where the third spot is a little ambiguous, it doesn't matter. Tina's Anticodon is flexible enough to recognize that CU codon, you still get leucine. The protein still works. It's like spelling, it's someone writes color or color. You know what they mean? The message still gets through despite the variation. You know, silly Brits, this wobble in the third position means the code is fault tolerant. Small errors don't necessarily break things. This third position, forgiveness by Rick. Well, it was actually discovered in 1966 by Francis Crick. Yes, that Francis Crick, the DNA double helix guy. He proposed something called the Wobble Hypothesis, and what he said was basically the ribosome is picky, but not that picky. The first two letters of a codon that is locked in, non-negotiable, Rick is checking those carefully. But the third letter, you know, there's wiggle room, Rick's like, uh, close enough. You're in. This means one, Tina can actually recognize multiple coons as long as the important part of the message matches. It's like reading someone's terrible handwriting, right? If the first few letters are clear, your brain fills in the rest. Is that an A or an O? Doesn't matter. The word is obviously color. Now, Crick realized this wasn't actually a flaw. It was a feature, and maybe the feature wobble made translation faster. More Tinas could recognize more codons, more forgiving. One misread letter wasn't necessarily the end of a protein and more resilient overall. Now, let me clarify that last one because I didn't get it at first. So what if you always needed CU You for leucine, always no wobble allowed. Any mutation to those three letters would probably destroy the protein. Remember, most mutations are deleterious, not superhero origin stories. So if every change to CU you is a dead end, that's it. No path forward. Evolution hits a wall, but. Enter the wobble. Weebles always wobble, but they don't fall down. I have no idea where that's from, but my parents said it all the time. So Wobble comes in and says, you know what? Let's change CUU to CUC. Same leucine protein still works now that CUC is floating around in the gene pool, and that's another chance at a beneficial mutation because at some point CUC might mutate to CCC and C. C. C is proline a completely different amino acid that changes the protein. Good change or bad change, who knows? But that CUU would have had to go through two mutations at the same time to get to C. C. C. Which is highly unlikely, much more likely is going to CUC in one step, and then C, C, C sometime later. Wobble gave evolution a safe stepping stone. Wobble. Lets evolution open more doors, more possibilities, more chances for something beneficial to sneak through. Okay, here's my best, go at an analogy for this one. Remember that movie Rookie of the Year? You know, picture's got a big butt and the picture looks to see if he does indeed have a big butt peak nineties comedy, if you haven't seen it. The kid breaks his arm and when the cast comes off, his tendons healed weird, super tight, and suddenly he's throwing a hundred mile an hour fastballs. He's 12 and pitching in the majors, well, they don't get into it, but what I always imagined is that this doctor had a slightly different technique in casting than other doctors and wasn't noticed in medical school. He passed with no problem because his cast still healed. Bones just fine. But one fateful day when this doctor cast Henry Rowen garter, he made a mistake. Now, here's the thing. He was the only doctor who could have made this mistake. All other doctors would have needed two changes to get to this point. But this particular doctor, he was already one step in. And that second change that led to a 12-year-old pitching in the major leagues beneficial mutation achieved. The doctor didn't invent a miracle cast. He just started from a slightly different place, and that different starting point opened the door to something impossible under the old rules. Okay. Now remember back in episode four when I said the you and RNA get swapped for the T and DNA, and I promised we'd talk about why. Well, here's the answer. It's all about error correction. Seas have a problem, and that problem is they like to spontaneously change into you. It's kind of like those burn away cake trends, like on the Surface it looks like one thing, maybe a nice floral design, but add a little heat and bam. Suddenly it's a picture of Shrek or something. You didn't ask for Shrek, but you got Shrek. That's C turning into you. This happens from heat time, random chemistry, and unfortunately for us, heat time random chemistry are all happening to your DNA thousands of times per day in every cell in RNA that's annoying but manageable. RNA is temporary. If something goes wrong, you just make another copy. It's no big deal. But D-N-A-D-N-A is the fireproof safe, the master archive the thing, everything else copies from. If DNA starts with a typo, that typo gets repeated over and over again. That's like starting the telephone game with the wrong phrase, you know? Somehow there's no fixing that downstream. So evolution needed a way to spot mistakes. And here's the trick. DNA doesn't use you at all. It uses T instead. Now, this didn't happen on purpose. It likely started with a simple mutation at first that didn't really change anything. T paired with a just as good as you. Proteins were still made, nothing broke. Now here's a bit of a niche explanation. Any of you remember Avatar and, no, not the Blue people, but Avatar. The Last Airbender, the Nickelodeon Cartoon Show. First off, amazing show. Second, do you remember at the end of season one, a kid in the Northern Water Tribe is going to dress up as a Fire Nation soldier and infiltrate their army? Only to find out from AKA that the uniform he has is in fact very outdated. If he goes into the Fire Nation Army wearing it, he'll be picked out immediately. That's what's happening with T. Once, DNA had a letter that clearly belonged there. Any U that showed up was obviously outta place. It stood out like the water tribe, kids outdated, fire nation uniform cells evolved. Repair enzymes that specifically hunt for you. In DNA to fix it. They recognize it as damage. That's the genius of this system. By using T instead of you, DNA created a built-in spell checker. Natural selection didn't plan this. It just kept the version that made fewer catastrophic mistakes. Evolution doesn't invent solutions, right? It just keeps accidents that turn out to be useful. So now if a C in DNA degrades into a u. The repair machinery immediately knows, uh, you in DNA. Absolutely not. That is a mistake. Remove it at once in RNA. If they see turns into a you, the system can't really tell. It's like texting Liv instead of love. Could be an autocorrect, could be intentional. That's hard to know. But if a u shows up in DNA, that's more like texting. What the duck? You know, it was autocorrected from something else, and that's why DNA uses T instead of you, not because T is better at pairing, but because it makes errors visible. And speaking of RNA, being temporary, let's talk about what happens to Mary after translation and its list has been read and protein made. So Mary gets made when DNA unzips and free RNA nucleotides assemble into a copy then Mary floats over to the ribosome and gets red and a protein gets made. Great. But then what does Mary just hang around? Like the Fs by a jukebox waiting for it to go out so we can do a cool little trick. No. No, she does not. Mary gets degraded, broken back down into individual nucleotides. Because the cell is life's biggest hippie. It's all about recycling and life needs this, right? The cell can't have Mary stuck in one form. That mean the same protein would be made over and over again. It's like if someone glued the letter magnets on fridges into only a few words. But your fridge making notes need more flexibility. You need more options. With individual letters, you are able to make whatever your little heart desires. If stuck in words, then you are severely limited. And a personal note here, when I was growing up, we actually did have words instead of letters, and I was extremely distraught. Because while my friends were having battles on their fridges via fun notes, you know, Sean is a butt face, or Ashley smells. While I could only do things like, uh, the cow jumped under the moon while admittedly hilarious, it wasn't the same. Now, this recyclable system is how cells regulate themselves. Same DNA in every cell of your body, but different marries made it different cells at different times. That's why a liver cell and a brain cell can have identical DNA and do completely different jobs. The genetic code, isn't about reading instructions. It's about controlling when and where those instructions get read. And Mary's ability to degrade and recycle is a huge part of that control. And the fact that we have the same DNA in every cell of our body has always been a wild thought to me. Basically, all our cells were given the same book. Different cells just bookmark different places, and Mr. NA Mary is a big part of that. All right, let's see how far we've come from the sloppy early system. Let's do a checkpoint here. All right. Anticodons Tina doesn't just show up randomly anymore. It has a three letter ID badge that physically pairs with Mary's code on lock and key. Way more accurate ribosomes. Rick isn't alone anymore. It's wrapped in helper proteins that hold everything steady. Keeps Mary in place and makes sure Tina lines up correctly. The party house got renovated into a factory redundancy. The code has built in error tolerance, multiple codons for the same amino acid wobble in the third position. Small mistakes don't break everything, and now there are more chances for beneficial mutations to rise. The U to T switch, DNA uses T instead of U, so the cell can toss out the U'S that have degraded from the C's. This is a built-in error detection, Mary turnover. Messages are temporary. Make them use them, recycle them, gives the cell flexibility and control. The genetic code went from toddler babbling to fluent speaker. Still not perfect. Nothing in biology ever is but good enough to build complex life. Now. Also, I wanted to mention something about Tina. You might be wondering if RNA is so fragile, how does Tina survive long enough to do her job? She doesn't have protein crew like Rick and isn't born to die like Mary or Harry Potter. Here's the trick. Tina folds back on itself. Parts with the strand are complimentary to the other parts, so Tina base pairs with herself A, with you G, with C, creating a sturdy little origami shape. She's basically, you know, giving herself a hug to stay together. Plus Tina's short only about 75 to 90 letters long less to flop around, you know, less to fall apart. So, you know, Rick has his protein support crew. Mary is temporary and disposable. And Tina, well, Tina holds her own shape through self-love and origami. Okay, so now we've got this refined system. Let's zoom out and look at the big picture. Information in biology flows in one direction, D-N-A-R-N-A protein. This is called the central dogma, and no, not dogma, like religious dogma. It was named in the 1950s by Francis Crick. He's back and he later publicly admitted he didn't really know what dogma meant. Uh, for those of you who were unsure, dogma. Implies unquestionable truth, belief, held without evidence, or you know, resistance to revision. And if you've gotten one thing from my podcast, I hope it is, that you understand that this is one of the worst terms you could use for anything in science. So the fact that this big helix finding wobble, hypothesizing, scientist, accidentally used the word is kind of hilarious. Not as hilarious as the fact that it stuck. And one of the most important things in biology has the word dogma. So the central dogma goes like this. DNA is the master copy, the archive, it stores the instructions, but doesn't do work itself. RNA is the messenger. It copies instructions from DNA and carries them to the ribosome. It's also the worker, TRNA delivers amino acids. RRNA does the chemistry. Protein is the product, the thing that actually does stuff in the cell. Enzymes, structures, signals, transports, proteins are the workhorses. Information flows from archive to messenger to product DNA to RNA to protein. That's the central dogma, and importantly, it doesn't flow backwards. Proteins don't write themselves back into DNA. You can't reverse engineer a protein into a gene. Well, well, mostly, there are some exceptions involving viruses and weird enzymes, but for normal cellular life, the central dogma holds and regardless of its dogma name. It was found with plenty of evidence. Information flows one way. This is the system. This is how life works. DNA stores it. RNA moves it. Proteins do it. And by the time this. System was locked in, refined and running smoothly. We had something special. We had a cell that could reliably store information, accurately, copy it, and precisely build the proteins it needed. We had the foundation for all life on earth. So here we are. The genetic code refined. The ribosome is built. DNA is stable and proofread. Mr. NA carries messages. TRNA delivers the amino acids. RRNA inside the ribosome built proteins and proteins do the work. All the pieces are in place. Somewhere around 3.5 to 4 billion years ago, there was a population of cells that had figured this all out. They weren't the first life. There was probably billions of years of messy failed experiments before them, but they were the ones that survived, the ones whose descendants would eventually become everything scientists call this population. Luca, the last universal common ancestor, it's not a single cell. That's a common misconception. Like there wasn't one cell that rose above the rest with like a spear and a loin cloth. Luca was probably a population of similar cells all sharing the same basic machinery, the same genetic code, same ribosome, same DNA to RNA to protein flow. And here's the wild part. We know Luca existed because of what all life shares today. Every living thing. Bacteria, ArcHa, plants, animals, fungi, axel lots, us all use the same genetic code. All make proteins the same way. A UG means methionine everywhere. UAA means stop everywhere the ribosome looks. Basically the same in e coli and in your cell. We all have the same factory. The only way that happens is if we all inherited it from the same source, one population, one system copied and passed down from billions of years. Luca wasn't sophisticated by modern standards. No nucleus, no mitochondria, no complex organelles, just. Membrane some DNA ribosomes and the genetic code. But Luca had everything it needed to survive, replicate, and evolve. And evolve. It did into every branch of the Tree of life. You are a direct descendant of Luca. So is every person you've ever met, every dog, tree, mushroom, bacterium in your gut, you get it? We're all family. Distant, ancient, weird family. Now, my friend texted me after she listened to the first episode. What if plants come from earth and animals come from space, mark and all. She was connecting the dots. Remember that? Some RNA may have formed on earth while some hitched a ride on media rights, and she wondered, what if different life came from different places? I loved this text. It was amazing. One of my favorite texts ever, because that's science. That's all science is. A curious person asking a question, they genuinely want answered. The nerdy science tattoos, the lab coats, pipettes, long nights, staring at data. The methods section that no one reads, all of it comes after. It's all fluff. It all starts with someone asking that first question and their desire to get the answer, there are no stupid questions. If a science teacher ever made you feel dumb for asking, one, they picked the wrong career unless you asked why. Male models, in which case, fair. Otherwise, keep asking questions. Keep being curious. You don't need a PhD to wonder about the world. Scientists aren't necessarily the smartest people in the room. They're the ones whose curiosity burns brightest. Everyone can be a scientist. That's so incredibly corny, but I honestly mean it. I mean, Aristotle, the guy we now call the father of biology, literally earned that title by walking around in ancient Greece and going, huh. That's interesting. Let me write that down. He dissected squids. He watched chick embryos developed. He cataloged hundreds of animals just because he was curious. That's it. That's the whole job. Being curious. Biology literally means the study of life. If you've ever been curious about life before, bam, you are a biologist. And my friend's question. I told her I loved it, but here's the answer. Plant and animal cells carry the exact same genetic code. Identical. Never altered. A UG means start in a sunflower. A UG means start in a cheetah. A UG means start in you. The only way that happens is if it all came from the same place. One origin, one ancestor, Luca. Alright, so let's bring this home. Last episode, life learned to speak a rough, sloppy error prone language of three letter codons. This episode, life learned to speak clearly. Tina got anticodons ID badges that match codons through base pairing lock and key accuracy. Rick got backup proteins wrapped around it. To form the ribosome a stable, efficient translation machine. The code got redundancy, multiple codons for each amino acid with wobble room in the third position, built in error tolerance. DNA got T instead of you, which allows the DNA to spot and fix. Damage, no use in here. Proofreading and Mary stayed temporary, made used. Recycle giving cells the flexibility to adapt. The central dogma emerged. DNA to RNA to protein information flows one direction. Archive to messenger to product, and with all these pieces refined and working together, Luca emerged the last universal common ancestor, the population of cells that would give rise to every living thing on earth, from random chemistry in a chaotic proto cell to a universal language spoken by all life. That's the journey we've been on, but we're not done. Luca is just the beginning From here, life is going to get wild. Cells are gonna get a little cannibalistic. Membranes are going to get complicated, and eventually something unprecedented is going to happen. But that's a story for another time. As always, I have a few notes for you before you, uh, click off. They're optional. Number one, i've made a super cool mistake. So I've been saying rib, zyme and ribosome. Apparently most people say rib zyme and ribosome. So I fixed it this episode and I apologize if any of you were laughed at by those classic jock like scientists. I'll take the heat for that one. Have them pen me a letter. I'll be here mispronouncing things, explaining the origin of life. You could say I'm like the, uh, chamal Leon of all explainers. That is a how I met your mother. Call out if you can't put your finger on it. Number two, one of my favorite TAs in college said she literally got into biology because she wanted to know if someone could actually become Spider-Man. My pontification earlier reminded me of her, and I thought you all might like that as well. Number three. So there are a handful of cells that don't share the exact same DNA, just so you know, red blood cells, eggs, sperm, cancer cells, and immune cells. But altogether, those make up roughly 1% of the cells in your body. So 99% of the time your cells have the exact same DNA thanks for joining me on this biological journey. I'm Jackie Mullins, and this has been from Cells to Us. How See you next time.