Episode Transcript
[00:00:00] Speaker A: Foreign.
Welcome to Bass by Bass, the papercast that brings genomics to you wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app.
[00:00:23] Speaker B: It's great to be here.
[00:00:24] Speaker A: I want to start today by asking you to visualize something. Picture DNA.
When I say that, you probably see that image from your high school textbook, right? The double helix, the iconic image.
[00:00:35] Speaker B: Yeah. It's always so perfect, so rigid, architectural.
[00:00:38] Speaker A: Almost exactly like a twisted ladder made of marble, just standing still in a museum. But the reality, and this is what we're finding out, is that if you could actually shrink down and stand inside a cell, DNA.
[00:00:51] Speaker B: Yeah.
[00:00:51] Speaker A: It wouldn't look like a statue at all.
[00:00:53] Speaker B: No, it's a.
It's much more like a mosh pit.
[00:00:56] Speaker A: A mosh pit. That's a great way to put it. It is a riling, dynamic, breathing machine. And here's the kicker. That motion isn't just random noise. It's actually the key to how you are alive right now.
[00:01:07] Speaker B: It's a fascinating engineering paradox when you really think about it. I mean, the genetic code, the A's, C's, G's and T's. It's locked on the inside of the helix, buried, completely buried, protected by all those hydrogen bonds, which is great for.
[00:01:20] Speaker A: You know, keeping it safe, but it's terrible for access. It's like keeping the blueprints for a building inside a safe that you've welded shut.
[00:01:28] Speaker B: How do the proteins that need to read the genes actually get to them?
[00:01:31] Speaker A: They can't. Not without help. For life to happen, that ladder, it has to break. The strands have to separate to expose the code. We call this breathing.
[00:01:41] Speaker B: But how it breathes, that has been the subject of this massive, polite, but very intense civil war in biophysics for over 30 years. It really has, and that's what hooked me. We think of science as just facts, but this was a total standoff. You had these two groups of brilliant scientists looking at the exact same molecule.
[00:02:02] Speaker A: Getting perfect data and coming to completely opposite conclusions. It was baffling.
[00:02:06] Speaker B: I mean, one group proved DNA opens all the time, and it stays open for a pretty long time.
[00:02:10] Speaker A: And the other group proved it almost never opens, and when it does, it snaps shut instantly.
[00:02:15] Speaker B: And we're not talking about some, you know, tiny decimal point error here. The numbers differed by a factor of a thousand. A thousand.
It's the difference between one second and almost 20 minutes. It's just. It's different reality.
[00:02:28] Speaker A: How can two truths exist at once?
[00:02:31] Speaker B: Well, that is the mystery. We're Getting into today. And the answer, believe it or not, is going to take us into physics that usually applies to like fiber optics or tsunamis.
[00:02:41] Speaker A: A traveling wave.
[00:02:42] Speaker B: Exactly.
[00:02:42] Speaker A: So settle in. Today we're doing a deep dive into the paper nucleic acid base pair open states by hydrogen hydrogen exchange.
[00:02:50] Speaker B: And we have to give a special recognition here to the author, S. Walter Englander. He's from the Perelman School of Medicine at the University of Pennsylvania.
[00:02:57] Speaker A: What I love about this paper is that he didn't just run another experiment to add to the fight, he basically acted as a peace negotiator. He stepped back, looked at 30 years of data and realized that maybe, maybe everyone was right.
[00:03:11] Speaker B: It's a masterclass in synthesis, really. He resolves this decades long paradox and, and in doing so, he introduces a completely new physical model for how our DNA actually works.
[00:03:21] Speaker A: Okay, so before we get to the solution, we have to really understand the war.
Let's set the stage, the background in context.
Why was this such a big deal back in the 90s?
[00:03:32] Speaker B: Well, the stakes were incredibly high. This whole base pair opening thing, it's fundamental. If we don't understand how DNA opens, we can't really say we understand how genes are read, copied or repaired.
[00:03:45] Speaker A: So in the red corner we had the tritium team.
[00:03:48] Speaker B: Right. This is the older established method. They used tritium labeling, which is just a radioactive form of hydrogen, to track what was going on. And they tested very, very long strands of DNA.
[00:03:58] Speaker A: Thousands of base pairs long.
[00:04:00] Speaker B: Exactly. Polynucleotides. And their data showed that DNA is, well, it's surprisingly loose.
[00:04:06] Speaker A: How loose?
[00:04:07] Speaker B: They found the base pairs were open about 1% of the time. Now, 1% sounds small, but. But for the molecule that holds the blueprint for life, that is a huge amount of exposure.
[00:04:16] Speaker A: And crucially, once it opened, it stayed.
[00:04:19] Speaker B: Open for milliseconds, which is an eternity in molecular time. It's like leaving your front door wide open for an hour every single day.
[00:04:26] Speaker A: Okay, but then in the blue corner comes the new tech nmr.
[00:04:32] Speaker B: Nuclear magnetic resonance. This was the high tech, high resolution approach. And the NMR scientists, they saw something totally different.
[00:04:40] Speaker A: What'd they see?
[00:04:41] Speaker B: They calculated that DNA is incredibly stable. According to their data, it only opens about 0.0001% of the time.
[00:04:48] Speaker A: That is a massive difference.
[00:04:50] Speaker B: And when it did open, it snapped shut in microseconds. So you have the tritium group seeing this floppy open structure and the NMR group seeing a rigid, tightly closed one.
[00:05:00] Speaker A: And because NMR was this shiny new toy, the scientific community sort of sided with them. Right. They figured the older data must be flawed.
[00:05:07] Speaker B: That was the consensus. Yeah. People assumed the tritium method was just, I don't know, misinterpreting some background noise. The textbook view became the NMR view. DNA is rigid, period.
[00:05:17] Speaker A: But Englander, our author, he didn't buy it. He basically said, chemistry doesn't lie. And this brings us to the methodology. He reanalyzed everything, Right?
[00:05:25] Speaker B: He didn't run a new test. He just looked closer at how they were measuring this, at the tool both camps were using, which was hydrogen exchange.
[00:05:32] Speaker A: Okay, I read the paper and this is where my brain started to cramp a little bit.
It gets into immuno and amino protons. Can we break this down? How does this molecular stopwatch actually work?
[00:05:44] Speaker B: Yeah, of course. Let's use an analogy. Imagine the DNA base pair is a bank.
Inside the bank, you have customers. Those are the protons we're measuring.
[00:05:53] Speaker A: Okay. Protons are customers. Got it.
[00:05:55] Speaker B: And outside on the street, you have people walking by. That's the surrounding water. The customers inside want to swap places with the people outside.
But they can only do it if the bank door is open.
[00:06:05] Speaker A: It makes sense. If the door is shut, nobody gets in or out.
[00:06:07] Speaker B: Precisely. So if you can measure how many people are swapping, you know how often and for how long that door is open.
[00:06:13] Speaker A: Simple enough.
[00:06:14] Speaker B: But here's the catch. There are two types of customers in this bank. We have the immunoprotons and the amino protons.
And they behave very differently.
[00:06:23] Speaker A: This is the part I missed. I mean, why does that matter? A proton is a proton, right?
[00:06:27] Speaker B: In physics, yeah.
But in chemistry, its environment is everything. Think of the immunoprotons as sprinters standing right at the door. The instant that door cracks open, boom. They sprint out and swap. It's immediate.
[00:06:40] Speaker A: So if you measure those sprinters, the imino protons, you're really measuring the exact moment the door opens.
[00:06:45] Speaker B: You're measuring the rate of opening, how frequently the opening event happens.
[00:06:49] Speaker A: Right. Okay, so what about the other ones, the aminoprotons?
[00:06:51] Speaker B: They're like the slow customers deep inside the vault. Even if the door opens, they don't just rush out, they're chemically slower to exchange. They might need the door to stay open for a while before they can manage to get out.
[00:07:04] Speaker A: So they're measuring something totally different.
[00:07:05] Speaker B: Or brisher, the equilibrium. Basically, what fraction of the total time the bank spends with its doors open. They don't care how fast it opens, they care how long it stays open.
[00:07:15] Speaker A: Okay, that clicks so Englander looks at the data from both teams, but he separates out these two types of protons and what does he find?
[00:07:23] Speaker B: He realizes the problem wasn't the protons, it was the bank itself.
The tritium team was studying these massive skyscraper sized banks, long DNA strands.
The NMR team, they were studying tiny little kiosks. Kiosks, short snippets of DNA, usually less than 15 base pairs long.
[00:07:42] Speaker A: Wait a second. So the only real difference in the experiments was the length of the DNA strand.
[00:07:46] Speaker B: That was the variable everyone just ignored.
Everyone assumed DNA is DNA no matter how long it is. Englander's big idea was, what if size matters? What if a long strand follows different physical laws than a short one?
[00:08:00] Speaker A: Which brings us to the key findings he proposes. There isn't just one way for DNA to open. There are two modes.
[00:08:08] Speaker B: Exactly. Mode one is what the NMR team saw in those short snippets. If you have a really short ladder, say 10 rungs, you can really only pop one rung out at a time.
[00:08:17] Speaker A: A single base pair just swinging out on its own.
[00:08:19] Speaker B: Yes. And here we have. Talk about stacking. We always think about the horizontal bonds, A to T, but the vertical strength is huge.
DNA bases are stacked on top of each other like powerful magnets.
[00:08:30] Speaker A: And to swing one out, you have to break that magnetic seal, which is.
[00:08:34] Speaker B: Energetically very, very expensive. The DNA hates doing it. So in these short strands, it pays this huge energy tax, POPS1 base open and then snaps it right back shut in microseconds to get stable again.
[00:08:45] Speaker A: So the NMR team wasn't wrong. They were just looking at a system that was too small and brittle to do anything else.
[00:08:50] Speaker B: Brittle is the perfect word. Now compare that to mode two, the long DNA. This is the breakthrough. Englander says that in a long helix, the DNA doesn't pop one base, it forms a bubble.
[00:09:02] Speaker A: A bubble.
[00:09:03] Speaker B: A coherent opening of about 10 base pairs all at once.
[00:09:08] Speaker A: Hold on, you just told me popping one base is really hard.
How can popping 10 be easier? That sounds like you would just shred the molecules.
[00:09:15] Speaker B: I know, it's totally counterintuitive. And this is the brilliant part. Inside this 10 pair bubble, the bases are disconnected from their partners. But, and this is the key, they stay stacked on top of their neighbors.
[00:09:28] Speaker A: Okay, I'm trying to picture this. So the ladder is split down the middle for a little bit, but the two side rails are still there and the rungs are still kind of lined up vertically.
[00:09:36] Speaker B: Imagine a stack of dinner plates. You can slide the middle five plates a Little to the side. They aren't perfectly aligned anymore, but they're still touching, still supported by the stack.
[00:09:45] Speaker A: So they keep that vertical magnetic contact.
Which means they don't have to pay that huge energy tax.
[00:09:51] Speaker B: Exactly. The energy cost per base is much, much lower. Which means the bubble can happen more often and it can stay open way longer for milliseconds. This is exactly what the tritium team saw all those years ago.
[00:10:04] Speaker A: And the NMR guys couldn't see this bubble.
Why?
[00:10:07] Speaker B: Because their DNA strands were too short. A bubble needs about 10 base pairs to form.
If your entire sample is only 12 base pairs long, you physically can't make one. The ends would just fray.
[00:10:19] Speaker A: It's like trying to do the wave in a stadium.
[00:10:21] Speaker B: But there are only three people in the stands.
[00:10:23] Speaker A: Right. You can't do the wave with three people.
[00:10:25] Speaker B: You need the crowd to sustain it. The NMR scientists were looking at a crowd of three and concluding, well, humans don't do waves.
They were missing the emergent property of the large system.
[00:10:35] Speaker A: This brings us to the coolest term in the whole paper. Englander calls this traveling bubble a soliton.
[00:10:41] Speaker B: Yes. A soliton is a concept from physics. It's a self reinforcing wave that maintains its shape as it moves.
[00:10:48] Speaker A: Like a tsunami wave crossing the ocean.
[00:10:50] Speaker B: Or a pulse of light in a fiber optic cable. Or a much simpler analogy, a rug bump.
[00:10:57] Speaker A: A rug bump? Yeah.
[00:10:58] Speaker B: Imagine you have a big heavy rug on the floor. If you want to move it, you don't drag the whole thing at once. You make a little wrinkle, a hump at one end.
[00:11:07] Speaker A: And you push the hump across the room.
[00:11:09] Speaker B: Exactly. The hump moves, but most of the rug stays put.
That hump is the soliton in our cells. This open bubble isn't stationary. It travels, it slides right along the double helix.
[00:11:21] Speaker A: So we have a moving window of open DNA sliding up and down our genes.
[00:11:25] Speaker B: That's right. It uses twisting energy to open the front of the bubble and releases that energy as the back closes. It's a mobile search window.
[00:11:32] Speaker A: Okay, this brings us to the discussion and implications section, because this is fascinating physics, but I'm a biologist at heart. Why should I care if my DNA has a traveling lump in it?
[00:11:42] Speaker B: Well, it completely changes how we think about genes being read. The old view was that a protein, say, transcription factor, had to walk along the closed DNA trying to pry it open every step of the way to check the code inside.
[00:11:54] Speaker A: That sounds exhausting. Like a burglar checking every single window on a block to See if one.
[00:11:58] Speaker B: Is unlocked and very slow. But with the solitin, the window opens.
[00:12:04] Speaker A: Itself and it moves.
[00:12:05] Speaker B: It moves. The protein doesn't have to pry anything. It can just kind of surf along the DNA and wait.
When the solitin wave passes by, boom. The code is exposed for a millisecond.
[00:12:15] Speaker A: The protein just peeks inside.
[00:12:17] Speaker B: It just peeks in. Is this my sequence? Nope. Okay. And the wave moves on. It turns a difficult mechanical problem into a simple search. The DNA is actively presenting its own code.
[00:12:28] Speaker A: The DNA isn't a passive library. It's an active display system. Wow.
[00:12:33] Speaker B: It creates a moving target for recognition.
[00:12:35] Speaker A: This makes me wonder about the flip side. We always think of genetic disease as a typo. You know, an A becomes a T. But if this wave is so critical, what happens if the wave breaks?
[00:12:46] Speaker B: That's one of the biggest questions this paper opens up for.
[00:12:50] Speaker A: Like, could you have a mutation that doesn't change the protein code, but it changes the stiffness of the DNA right there?
[00:12:57] Speaker B: Absolutely. If a section of DNA is too rigid or it has some chemical modification on it, that solitin might just crash.
[00:13:05] Speaker A: And if the wave crashes, the code never gets exposed.
[00:13:08] Speaker B: So the gene is effectively silenced. It's there, the sequence is perfect, but it's completely unreadable.
[00:13:15] Speaker A: That could explain so many diseases where we can't find the typo. We've been looking for spelling errors when we should have been looking for, for mechanical failures.
[00:13:24] Speaker B: It opens up a whole new field, really, the pathology of DNA mechanics. And it has huge implications for drug design too.
[00:13:31] Speaker A: How so?
[00:13:32] Speaker B: Well, a lot of drugs, especially for cancer, work by binding to DNA to stop it from being copied. If we understand these waves are constantly happening, maybe we could design a drug that it doesn't just bind anywhere, but it specifically traps the wave.
[00:13:46] Speaker A: Like putting a heavy rock in front of that rug bump so it can't move.
[00:13:49] Speaker B: Exactly. You freeze the salt and you freeze the cell's ability to read its own map. For a cancer cell, that could be a death sentence. It gives us a brand new target.
[00:13:57] Speaker A: It's just incredible to think this was missed for 30 years because our samples were too short.
[00:14:01] Speaker B: It's a real lesson in reductionism, isn't it? Sometimes when you break a system down to its smallest parts to make it simple, you. You lose the very thing that makes it work.
You can't study a wave in a cup of water. You need the ocean.
[00:14:14] Speaker A: So what's the take home message here? If you remember one thing from this deep dive, what should it be?
[00:14:19] Speaker B: I think it's this.
We have to stop thinking of DNA as a simple switch, either open or closed. It's a whole spectrum of motion. You have the fast, brittle single bass flutters and you have these slow, robust traveling waves.
[00:14:35] Speaker A: And that solitan wave is probably the fundamental mechanism that makes our genetic code accessible. It's the heartbeat of the genome.
[00:14:41] Speaker B: It perfectly connects the physics of energy waves to the biology of who we are. It's a beautiful, unifying idea.
[00:14:48] Speaker A: I want to leave everyone with a final thought. If our DNA is constantly being scanned by these traveling waves, is it possible that our environment, things like stress or diet or even temperature could affect the frequency or the speed of these waves?
Are we tuning the radio of our own genome just by how we live?
[00:15:04] Speaker B: That's a fascinating thought. Dynamic epigenetics. Not just chemical tags, but changing the actual rhythm of the DNA itself.
[00:15:12] Speaker A: Something to think about next time you feel like you're just sitting still inside, you're actually a mosh pit of traveling waves.
This episode was based on an Open Access article under the CC BY 4.0 license. You can find a direct link to the paper and the license in our episode description. If you enjoyed this, follow or subscribe in your podcast app and leave a five star rating. If you'd like to support our work, use the donation link in the description. Now. Stay with us for an original track created especially for this episode and inspired by the article you've just heard about. Thanks for listening and join us next time as we explore more science base by base.
[00:16:10] Speaker C: In a quiet healing under sugar and salt I hold my letters like a.
[00:16:19] Speaker B: H.
[00:16:21] Speaker C: What a nocturnal softly trading light for light A whisper motion in the edge of night Some doors just flicker gone before you see Some doors they breathe in making room in me.
[00:16:46] Speaker B: Two.
[00:16:46] Speaker C: Kinds of truth in the same old frame A flash in the dark and in a traveling flame if you only watch one window you'll swear it's wrong but the molecule keeps singing Both songs I'm 1% open Let the river in a loop on the ladder where the world begin Then I snap back fast like a spark on skin still I'm 1% open that there is microsecond heartbeat millisecond wave two ways to be restless two ways to be brave.
There's a tiny tremble wrong, let's go A blink of unbinding A quick hello There's a longer doorway Take steps wide holding on to balance while it slips and slides it wanders down the sequence back and forth Searching for a name measuring its words Two kinds of truth in the same old frame A fragile little crack in a Roman refrain Small can't hold the wire While I drowns out the small so each experiment hears its own call I'm 1% open let the river in a loop on the ladder where the world begins Then I snap back fast Like a spark on skin still I'm 1% open let the river in microser my heartbeat Middle of second wave Two ways to be restless Two ways to be brave.
Don't try the lock with lying hands don't blame the mirror for shifting sands Wait for the wave that walks the line A moving window in real time it scans the dark for a place to land then close Nose is gentle like a he I'm 1% open let the river in a loop on the ladder where the world begin Then I snap back fast Like a spark on skin still I'm 1% open let the river Microsecond heartbeat Millisecond wave same double healing two kinds of brave oh I'm 1% open.
One person open.
One person open.
