Episode Transcript
[00:00:20] Speaker A: Welcome to Base 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. Appreciate.
[00:00:29] Speaker B: Yeah, thanks for tuning in, everyone.
[00:00:31] Speaker A: So today we aren't just looking at a normal paper. We are looking at what is essentially a heist.
[00:00:36] Speaker B: A heist, I like that.
[00:00:38] Speaker A: But, you know, not a bank robbery. We're talking about a break in at the absolute most secure facility in biology, which is the cell nucleus.
[00:00:45] Speaker B: Right. And the intruder isn't some foreign virus or a new chemical toxin. Yeah, it's an inside job.
[00:00:52] Speaker A: Exactly. I want to start with an image for everyone listening. Picture the nucleus as this high end film editing suite.
[00:00:59] Speaker B: Okay.
[00:01:00] Speaker A: You got the director, you've got the editors and miles of raw footage. That footage is your pre mRNA, Right?
[00:01:06] Speaker B: The unedited script of the cell.
[00:01:07] Speaker A: Yeah. And the job in that room is super precise. They have to cut out the bad takes, the bloopers, the clapperboards, basically the introns. Right. And then they splice together the perfect scenes, the exons, to make a blockbuster movie. And that movie is the mature MRNA that actually goes out to make proteins.
[00:01:25] Speaker B: It's a great analogy because the stakes in that editing room are incredibly high. I mean, if you leave a blooper in a Hollywood movie, you get a bad review. But if you leave an intron in
[00:01:36] Speaker A: an MRNA sequence, you get a dysregulated cell.
[00:01:39] Speaker B: Exactly. You get disease.
[00:01:41] Speaker A: Usually the editors, the splice system machinery, they are infallible. They know exactly where to snip.
[00:01:46] Speaker B: Most of the time, yeah.
[00:01:47] Speaker A: But in today's deep dive, we're introducing a ghost. A character from the studio's distant past. Something that hasn't worked there in millions of years.
[00:01:56] Speaker B: And it just walks into the editing room.
[00:01:58] Speaker A: Walks. Right.
Locks the door and starts messing with the equipment.
[00:02:01] Speaker B: It hides the scissors.
[00:02:03] Speaker A: Yeah. It spills coffee on the console and
[00:02:05] Speaker B: suddenly the movie goes out with all the deleted scenes still in it.
[00:02:09] Speaker A: And the result isn't just a mess. It's a biological catastrophe that literally drives the cell to grow uncontrollably. We are talking about cancer.
[00:02:18] Speaker B: This is the central mystery we're unpacking today. We're looking at how a tiny piece of genetic code, something we used to dismiss as just genomic noise. Right? How it wakes up, infiltrates that editing room and systematically sabotages the machinery so
[00:02:34] Speaker A: to get right into it. The paper that uncovered this sabotage is titled Cancer associated snar. A non coding rna, interact with core splicing machinery and disrupts processing of MRNA subpopulations.
[00:02:47] Speaker B: It's a bit of a dense title.
[00:02:49] Speaker A: It is, but the findings are crystal clear.
Today we really celebrate the work of Sihang Zhu, Kevin Van Bortel and their team at the University of Illinois, Urbana Champaign.
[00:02:59] Speaker B: Yeah, fantastic work.
[00:03:00] Speaker A: Published in Nature Communications in November 2025.
[00:03:04] Speaker B: It's such a fascinating read because it really feels like it bridges two islands in genomics that, you know, they don't trade with each other very often.
[00:03:11] Speaker A: What do you mean by that?
[00:03:13] Speaker B: Well, on one island you have the dark genome people studying junk rna, and on the other you have the structural biologists looking at the nuts and bolts of tumor growth.
[00:03:22] Speaker A: Ah, I see.
[00:03:23] Speaker B: And this paper builds the bridge. It shows that the junk is actually jamming the nuts and bolts.
[00:03:27] Speaker A: So let's introduce the saboteur. The paper calls it SNAR A. When I first saw that, I honestly thought of a pirate. Snar.
[00:03:33] Speaker B: Yeah, it does sound like that. But break down the acronym for us.
[00:03:36] Speaker A: Right, so it stands for Small NF90 Associated RNA Isoform A.
[00:03:42] Speaker B: Let's just stick to SNAR A to keep our tongues untied.
[00:03:45] Speaker A: Good call. The headline here is that it is a non coding rna.
It's not a blueprint. It doesn't translate into a protein.
[00:03:52] Speaker B: No, it's a functional tool, or in this case, a weapon made entirely of rna.
[00:03:56] Speaker A: And here's the part that really caught my attention. In the background.
SNARRA is a hominid specific gene, which is wild. It is. That means my dog doesn't have it. The lab mice we use to cure cancer, they don't have it either.
[00:04:10] Speaker B: That is a massive point for anyone listening who works in animal models. Yeah. SNARI evolved from ALU elements.
[00:04:16] Speaker A: Remind us what those are.
[00:04:18] Speaker B: They're retrotransposons. Think of them as jumping genes that act like copy paste code in the genome. They're incredibly common in primates, but completely absent in rodents.
[00:04:28] Speaker A: So this explains a lot of frustration in the field.
[00:04:30] Speaker B: Exactly. If you've been trying to study this specific pathway in a mouse model, you're basically looking for a ghost that isn't there. This is a uniquely human. Well. And great ape problem.
[00:04:41] Speaker A: It really adds a layer of speakiness to it. It's a ghost in our specific machine.
[00:04:46] Speaker B: Yeah.
[00:04:46] Speaker A: So under normal circumstances, if I'm a healthy adult, where is SNAR A? Hanging out.
Is it floating around in my liver or my brain?
[00:04:56] Speaker B: Hopefully not in a healthy adult. Snore is strictly confined to the testes.
[00:05:00] Speaker A: Okay.
[00:05:01] Speaker B: It's highly developmentally regulated, but. And here is the Cancer associated part of the title. In many types of solid tumors, it re emerges.
[00:05:09] Speaker A: It's like a zombie gene.
[00:05:10] Speaker B: That's exactly what it is. It's supposed to be dead and buried, tightly locked away in the testes. But the tumor finds a way to wake it up.
[00:05:16] Speaker A: Okay, so we have the setup. We knew before this Deep Dive that snore levels spike in tumors. We also knew that if you artificially pump snorae into a cell, that cell starts proliferating like crazy.
[00:05:28] Speaker B: Correct. We have the crime and the suspect. High snore equals rapid growth.
[00:05:32] Speaker A: But we had a massive scientific gap.
[00:05:34] Speaker B: Right. We didn't have the weapon. We had absolutely no idea how an RNA molecule was forcing the cell to divide.
[00:05:40] Speaker A: Is it acting like a sponge to soak up other molecules? Is it acting like a guide? Is it scaffolding?
[00:05:45] Speaker B: Is it exactly what is it physically touching in the darkness of the nucleus?
That is the detective story this team undertook.
[00:05:53] Speaker A: I loved the methodology section here because it felt like a dragnet. They didn't just look for one thing. They cast a really wide net.
[00:06:00] Speaker B: Yeah.
[00:06:01] Speaker A: Walk us through this fishing expedition.
[00:06:03] Speaker B: Fishing expedition is a perfect description. They started with an RNA pulldown.
Imagine taking a strand of Snaray and attaching a chemical hook to it.
[00:06:12] Speaker A: In this case, biotin, right?
[00:06:13] Speaker B: Yes, biotin. They lower this hook into supacella satellite. Basically the blended contents of THP1 cells and see what bites.
[00:06:23] Speaker A: Like lowering a magnet into a bucket of bolts.
[00:06:26] Speaker B: Precisely. They pulled the snari back out and analyze everything stuck to it using mass spectrometry.
[00:06:32] Speaker A: Which gives them an unbiased list of potential partners.
[00:06:35] Speaker B: Right. They aren't guessing. They are letting the chemistry tell them the answer.
[00:06:39] Speaker A: And to be sure, this wasn't just, you know, a test tube artifact. They validated it with RAP RNA aminoprocess.
[00:06:44] Speaker B: Yes, but knowing what it touches is different from knowing where it touches them. Yeah. Context is everything in cell biology.
[00:06:51] Speaker A: It is. So for the visual evidence, they brought out the big HCR RNA and fish,
[00:06:56] Speaker B: which wins the award for the most complicated acronym of the Deep Dive.
[00:07:00] Speaker A: Hybridization. Chain reaction RNA fluorescence In situ hybridization. It's a mouthful.
[00:07:05] Speaker B: It is. But the result is beautiful. It allows researchers to light up the snara inside a living cell with fluorescence.
[00:07:13] Speaker A: So they can actually see it.
[00:07:14] Speaker B: Exactly. They could map its GPS coordinates inside the nucleus down to the subcellular level.
[00:07:19] Speaker A: And finally, just to completely lock it
[00:07:21] Speaker B: down, they used crosslinking immunoprecipitation. They used UV light to instantly freeze or cross link proteins to The RNA
[00:07:30] Speaker A: they are touching, catching them in the
[00:07:32] Speaker B: act, patching them red handed. It proves these two molecules aren't just in the same room. They are literally shaking hands.
[00:07:37] Speaker A: Okay, the trap is set. They pull up the net. Now, given the name small NF90 associated RNA, I assume they expected to find the protein NF90.
[00:07:46] Speaker B: They did, and they found it. But that wasn't the headline.
The mass spec threw them a massive curveball. The strongest interactions weren't with NF90. They were with splicing factors.
[00:07:56] Speaker A: The film editors.
[00:07:57] Speaker B: The film editors, specifically a protein called SF3B2.
[00:08:02] Speaker A: SF3B2.
Let's create a mental tag for this protein so we don't get lost in the Alphabet soup here.
What is its day job?
[00:08:09] Speaker B: SF3B2 is a core component of the U2 SNRNP.
[00:08:13] Speaker A: Okay.
[00:08:14] Speaker B: The U2 SNRMP is one of the main gears in the spliceysome, the machine that identifies the branch point of the intron. So in our movie analogy, essentially SF3B2 is the guy who holds the film strip steady so the cutter knows exactly where to slice. Got it. If SF3B2 isn't there, or if it's distracted, the cut doesn't happen.
[00:08:34] Speaker A: So this junk RNA from our evolutionary past is heading straight for the main control panel of the splicing machine.
[00:08:40] Speaker B: And the GPS data. The SFH imaging confirmed it. They saw SNARRI localizing specifically to nuclear speckles.
[00:08:47] Speaker A: Nuclear speckles that sound like a candy,
[00:08:49] Speaker B: but I know it's far from it. Think of nuclear speckles as the factory floor or the tool shed where the spicing factors are stored and concentrated. SNARI doesn't just float randomly. It infiltrates the specific zone where the splicing machinery is assembled.
[00:09:01] Speaker A: So it breaks into the toolshed and finds the SF3B2 protein. What happens then? Is it a hug or a tackle?
[00:09:09] Speaker B: It's an abduction.
[00:09:10] Speaker A: Whoa.
[00:09:10] Speaker B: The researchers found that when SNARA levels are high, the efficiency of splicing absolutely plummets. They observed a massive increase in intron retention.
[00:09:19] Speaker A: Intron retention. Going back to our movie analogy, these are the deleted scenes. The junk footage that is supposed to end up on the cutting room floor.
[00:09:26] Speaker B: Exactly. And this is crucial for you, the listener, to visualize. An intron often contains stop codons or just gibberish sequences.
[00:09:35] Speaker A: Right.
[00:09:36] Speaker B: If you leave an intron in the final mRNA, the ribosome, the protein printer will hit that gibberish and just stop printing.
[00:09:42] Speaker A: Oh, wow.
[00:09:42] Speaker B: You end up with a truncated, broken, completely useless protein. Or the MRNA Itself gets flagged as garbage by the cell and destroyed.
[00:09:50] Speaker A: So Snorri gums up the machine. The introns get left in, and the instructions for the cell become unreadable.
[00:09:57] Speaker B: And here's the most insidious part. High levels of SNARE actually caused the overall protein levels of its partner, SF3B2, to drop.
[00:10:04] Speaker A: Wait, so it binds to the protein and destroys it?
[00:10:06] Speaker B: It destabilizes.
Seems that by binding to SF3B2, Snarra disrupts the complex that keeps SF3B2 stable. So the more SNR A you have, the less functional splicing machinery you have.
[00:10:20] Speaker A: The ghost creates so much chaos that the editor just quits?
[00:10:23] Speaker B: Essentially, yes.
[00:10:24] Speaker A: But this brings me to a huge paradox. If you destroy the splicing machinery, you break the cell. The cell shouldn't be able to make proteins. It should die.
[00:10:31] Speaker B: Right.
[00:10:32] Speaker A: But we started this deep dive by saying Snore A makes cancer cells grow. How does breaking the engine make the car go faster?
[00:10:40] Speaker B: That is the million dollar question. And the answer lies in specificity.
[00:10:43] Speaker A: Specificity.
[00:10:44] Speaker B: It turns out Snore A is not a shotgun. It's a sniper. It doesn't break all splicing. It disproportionately affects a specific subset of MRNA's that are hypersensitive to SF3B2 levels.
[00:10:56] Speaker A: So it's cutting the brake lines, but leaving the accelerator intact.
[00:10:59] Speaker B: That is the perfect analogy.
The researchers looked at which genes were being messed up by this intron retention, and one of the top hits was
[00:11:06] Speaker A: ogfr, the opioid growth factor receptor. I'm guessing from the name that OGFR has something to do with growth.
[00:11:13] Speaker B: It's a tumor suppressor. Under normal conditions, OGFR regulates cell replication. It says, whoa, slow down. We have enough cells. Here it is. The brake pedal.
[00:11:22] Speaker A: I see the mechanism now. Hysnara leads to sloppy splicing of the OGFR gene. The cell produces broken OGFR mRNA, which gets trashed.
[00:11:32] Speaker B: And no OGFR protein means no brake puddle.
[00:11:34] Speaker A: And without the brakes, the car accelerates. The tumor grows. By sabotaging the splicing of specific tumor suppressors, SNARE tips the balance toward proliferation.
[00:11:45] Speaker B: It's sand in the gears, but it's very targeted sand. It selects for cancer survival.
[00:11:49] Speaker A: That is incredibly elegant in a terrifying way. But there was another twist in the phenotypic data that I found really surprising.
[00:11:56] Speaker B: The migration data.
[00:11:57] Speaker A: Yes. We've established that snare A makes the tumor grow. But when they knocked it down and they removed the snare using snrna, the cells didn't just stop Growing. They started moving.
[00:12:07] Speaker B: Yes. This was a fascinating trade off. When snarn A was removed, proliferation went down, but migration actually went up.
[00:12:13] Speaker A: So the cells stopped dividing but started spreading.
[00:12:15] Speaker B: Exactly. It suggests that SNARE locks the cell into a growth state rather than a metastasis state.
Biology is often a series of trade offs. You can build a fortress or you can send out scouts, but it's really hard to do both at maximum capacity simultaneously.
[00:12:31] Speaker A: So a tumor with high snore is likely a large, rapidly expanding mass, but perhaps less likely to have micrometastases spreading out.
[00:12:40] Speaker B: Potentially. It implies the SNORRI is a lever. The cancer pulls when it wants to bulk up.
[00:12:44] Speaker A: Let's zoom out to the patient. This is all great molecular detective work in a petri dish, but does it hold up in real people?
[00:12:51] Speaker B: The team analyzed data from tcga, the Cancer Genome Atlas. They look at patient survival relative to SNARE expression.
[00:12:58] Speaker A: And the verdict?
[00:12:59] Speaker B: Guilty. SNARA activity is a strong negative prognostic factor.
[00:13:04] Speaker A: Meaning worse outcomes.
[00:13:05] Speaker B: Yes. Patients whose tumors have high levels of this RNA tend to have significantly worse survival rates.
[00:13:12] Speaker A: That really brings it home. This isn't just obscure biochemistry. If this ghost is active in your tumor, your outlook is statistically worse.
[00:13:19] Speaker B: It connects the mechanism directly to clinical outcomes.
However, we have to be responsible scientists here and note the limitations.
[00:13:27] Speaker A: Always.
Where are the blind spots in this study?
[00:13:30] Speaker B: Well, most of the functional work here was done in vitro. They use cell lines like AGK293TE and A549 lung cancer cells.
[00:13:38] Speaker A: Standard workhorses in the lab.
[00:13:40] Speaker B: Right, but a plastic dish is not a human body.
[00:13:42] Speaker A: And we mentioned that snare is hominid specific. So we can't just breed a knockout mouse to test this.
[00:13:49] Speaker B: Exactly. That makes in vivo testing much harder. You have to use xenografts implanting human
[00:13:54] Speaker A: tumor cells into mice.
[00:13:56] Speaker B: Right, which the study did to some extent. But understanding the full systemic interplay is definitely the next big hurdle.
[00:14:02] Speaker A: There is also that dark genome angle we touched on earlier.
[00:14:05] Speaker B: Right. This study is a proof of concept for a pretty terrifying idea. We used to think of the non coding regions of DNA, which make up about 98% of our genome, as junk, just evolutionary debris.
[00:14:15] Speaker A: But SNORRI proves that the debris is armed.
[00:14:18] Speaker B: It suggests the junk is more like a warehouse of dormant tools. Some might be useless, sure, but others, like snarre, are retrotransposons that the cell has silenced for a reason.
[00:14:29] Speaker A: Yeah.
[00:14:29] Speaker B: When cancer dysregulates the genome, it's not just breaking genes, it's unlocking this warehouse.
[00:14:35] Speaker A: It's like the tumor is scavenging through the trash to find weapons that the body threw away millions of years ago.
[00:14:41] Speaker B: That is a chilling but very accurate way to put it.
[00:14:43] Speaker A: So if we had to distill this entire deep dive into a single mental model for the listener, how would you summarize the heist of the spliceism?
[00:14:51] Speaker B: I'd say this. We have a hominid specific RNA called snar A.
It's supposed to be silent, but cancer wakes it up. It infiltrates the nuclear splicing factories, the speckles, and hugs a key protein called SF3B2 to death.
[00:15:06] Speaker A: Right.
[00:15:06] Speaker B: This sabotage breaks the splicing machine, causing it to leave junk code in the mRNA. And this specifically disables the body's braking systems like ogfr, allowing the tumor to grow unchecked.
[00:15:17] Speaker A: It's a molecular hack, a denial of service attack on the cell's quality control.
[00:15:21] Speaker B: A very effective one. And it's a reminder that in cancer biology, nothing is ever truly noise.
[00:15:27] Speaker A: It really forces a provocative question for everyone listening. If Scenari is just one example, if this one tiny piece of non coding RNA can evolve to hack the fundamental machinery of life to drive cancer, what other silent genes are sitting in our
[00:15:45] Speaker B: DNA right now waiting for the right trigger?
[00:15:47] Speaker A: Exactly. Waiting to wake up and rewrite the rules.
[00:15:49] Speaker B: That is the question that keeps geneticists up at night.
The dark genome is likely full of these saboteurs. We've just found the first one.
[00:15:57] Speaker A: On that slightly terrifying but fascinating note, we'll wrap up this deep dive.
[00:16:00] Speaker B: It's been a great discussion.
[00:16:02] Speaker A: This episode was based on an Open Access article under the CCBY 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. Bass by bass.
[00:16:50] Speaker C: Long nights under bright screams A tiny thread drifts near the light A whisper called Snara folds into the cross crowd of moving parts it slips beside the speckles where the old machines decide the
[00:17:17] Speaker B: cut
[00:17:20] Speaker C: Silent knots hold back the seam in way like shadow doors.
A single voice can bend a pattern Slow the rhythm of the heart we hear the whisper we trace the frame A secret written in the splice Hands of the unseen? Pull the river the thing edges in so long instead of me? At the sea we'll make the broken language? Broad.
Proteins falter, Messages stall?
The cell keeps turning? Now new scores, tiny changes? Push the tide and make the tower rise a little more?
Yet in the hush there's an answer Hidden in the folds of coal?
Turn back the needle?
Tune the course?
Call all the scattered parts adore? Restore the faithful kind?
Let the older voices speak again?
From speckled to the open wire?
Clarity will find a way?
We hear the whistling? Trace the thread the secret learns so hands of the unseen Yield the tangled light?
Release their heart?
Stand with me at the seam?
We sing the splice into the Sa.
Sam.
