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RNA Takes Over

science.org

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Katalin Karikó's 2005 paper provides some insight into a few of the stranger aspects of RNA's interaction with the immune system. You can't just put all RNA, or even all mRNA, in a bucket and consider it all the same. Slight variations can change biochemical reactivity activating or avoiding an immune response.

https://doi.org/10.1016/j.immuni.2005.06.008

I get chills reading that paper. I know that without mRNA vaccines we’d have plenty of alternatives, but for a while there it was really saving the world.

What gives me chills is that she was denied tenure at the University of Pennsylvania.

Fortunately she got a side gig, and managed to stay on as an adjunct. She was able to keep working on mRNA rather than having to be a waiter or an Uber driver or something like that.

Now she's on just about everyone's short list for a Nobel Prize in the not-too-distant future.

I was thinking this was a surprisingly readable and irreverent science article. Then I saw it was Derek Lowe. The man is a gem.

The author, when especially "authoritative", should be specified with the title.

The trend of discovering biological purposes for what were once termed 'junk' DNA (which these RNA are transcribed from) continues.

In addition to the improved understanding of our physical nature, it will be exciting to see what applications are developed for targeting or tricking-out these novel cellular components for pharmaceutical and biotechnological purposes. They are sure to be significant, if our experience with the RNA tech employed in the modeRNA and Pfizer vaccines are any indication.

Personally, as someone who finished his biochemistry degree 2 decades ago (and has mostly worked on the software side of things since), I'm excited for what we'll be able to do with fuller understanding of this molecular machinery, and plan to pivot back into biotech over the next decade.

It seems that we find more and more 'junk' DNA to not be junk. Whoever was quick to label it 'junk DNA' did so in haste. It would have been a lot more humble to label it 'DNA of unknown function'.

Well we did rename swamps to wetlands.

A swamp is a type of wetland. They weren't renamed.

Well, there is supposedly a distinction between swamps (which are dominated by trees), marshes (which are dominated by grass) and bogs (which have a pH differing from 7). This is already kind of a weird classification scheme, since the trait that defines a bog is so wildly different from the trait that defines swamps and marshes. And then, if you believe in this scheme, "wetlands" is the generic term referring to all of them.

But 1cvmask is actually correct that the generic term was (and still is, outside of specialized scientific terminology) "swamp", and pushing the approach of my earlier paragraph constitutes a renaming.

Where does muskeg fit in all of this? Also salt marshes which while they may have grasses, are different ecosystems.

Sometimes a riparian estuary is just a riparian estuary... Let's call a fen a fen and be done with it...

Would not a bayou by any other name be as mucky?

You made me curious and some quick duckduckgo-ing led me to a biologists involved-if-not-comprehensive investigation of the origins of the term [0].

Long story short, it probably dates to late 1950s Cambridge and may have originated with Francis Crick, co-discoverer of the structure of DNA. Of relevance is that it preceded the discovery of mRNA, dating to a time when all RNA was thought to be ribosomal DNA. At that time the prevailing theory was that DNA codes for RNA that is incorporated into the ribosome (which then makes proteins). Because the amount of RNA code in the ribosome was clearly much less than the amount of DNA code in the genome, the implication was that much of the genome did not code anything, simply as a matter of mathematical difference. The term was controversial early on, and it might even have been coined to be so, though that's less clear.

[0] https://judgestarling.tumblr.com/post/667709690372849664/the...

"dark dna"

If most dna were junk

IIRC it was in jest, and then taken as "serious" by mainstream audience, like "god paricle" or "al gore invented the internet".

> "al gore invented the internet"

This is politics: If you can claim the Other Guy said something stupid, you can score points against the Other Side.

I mean Al Gore did say something stupid. I don't think he intended it to come across the way it did, but he did say it.

“ During my service in the United States Congress, I took the initiative in creating the Internet. I took the initiative in moving forward a whole range of initiatives that have proven to be important to our country’s economic growth and environmental protection, improvements in our educational system.”

That’s what he said. It was not stupid or inaccurate.

"I took the initiative in creating the Internet"

That's stupid and inaccurate. It infers the internet would not exist without his efforts. That's clearly not true.

If he had said "I took the initiative to drive development of the internet" then sure. But "creating" it? No.

you are right about this, i think HN posted an article on “junk” dna not being “junk” dna after all. this was about a month ago, it may have been on news.google.com if it was not on here, having read science breakthrough stuff throughout the years i was never convinced of that term and was more than cautious when tech subs started talking about how crispr alters “junk” dna, the general consensus before the pandemic was, “this is cool, but we must be careful, this technology may cause unexpected side effects” but during the pandemic or the peak of it, people were like “canon ball”, all caution to the wind. or seemed like caution was thrown to the wind. it’s surprising how fast we adopted this technology but we still gotta question if there is gonna be long term issues. there’s nothing wrong with questioning science, that’s actually what science is about.

While new discoveries of biological function are fascinating, I don't think it follows that we are overturning the idea of junk DNA (however the phrase was coined). More likely we are converging towards an understanding where most of the genome really is non-functional. Here's a recent accounting [1] of known function suggesting 90% is junk. I wonder how much this differs from our understanding of decades ago, it really may not have changed much at least in terms of broad accounting. Now the potential significance of those little fractional bits of recently uncovered function, well that's a different discussion and more aligned with the original article, which I don't think mentioned junk anyway.

[1] https://sandwalk.blogspot.com/2021/11/whats-in-your-genome-2...

Molecular biology education needs more funding. Teaching it at scale (and more importantly, communicating new discoveries outside of textbooks) still remains a challenge. Keeping up with the field without reading papers is much harder compared to CS/ML where almost every ML engineer maintains a blog.

I'm in a similar situation but a decade removed. I'm not sure I even remember what I learned previously - how have you retained anything after 2 decades?

I try to read journal papers every now and then, usually when investigating the source of some news story, or when digging down into the molecular details of a personal health interest. Somewhat contrary to the theme of TFA, I've found that my 20 year old training has provided good mileage in terms of understanding current research. Much of the overarching theory of molecular biology hasn't changed in that time, and a lot of the same techniques are still used, if often miniaturized and scaled, e.g. microarray methods for things I learned to do using blots. For when I find a gap in my knowledge, modern literature search tech facilitates digging down to find related papers that describe newer theories or ones that describe new methods. Often I'll find references to review papers which are essentially designed to get one up to speed on a topic. If anything papers are easier to access now than back when I was in university, wink wink.

Oh, and there are definitely quite a few bored biochemists contributing serious detail to select wikipedia articles. With grain of salt in hand, I've found some pretty high quality descriptions (in terms of detail and ease of understanding) of molecular pathways peppered throughout articles on various topics, which can serve as decent starting points for diving into the literature on those topics.

I'm a far cry from considering myself current on the latest research, but I feel not too far behind and that I can catch up quickly when needed.

Things are pretty different from what I was taught in high school now, or perhaps just more detailed. Some examples:

Protein and ligand are like a lock and a key >>> Some proteins have no intrinsic shape and wrap around ligands or other proteins. Maybe there is RNA involved as well.

The cell membrane is like a soap bubble >>> Different lipids cluster together to form raft like structures with different content based on lipid composition.

DNA -> RNA -> Protein >>> DNA <-> RNA -> Protein.

We have a lot of Junk DNA >>> We shouldn't call it junk DNA, it plays a role in regulation of the exome, wrapping DNA around chromatin and probably plays a lot more roles on a larger scale, equally or more important than the exome even.

Optical microscopes have resolution a limit of about lambda[the wavelength of the used light]/2 >>> We have super-resolution optical microscopy now (ie STED, STORM/PALM, SMM probably more and better, I left the field 10 years ago).

The immune system plays no role in cancer >>> We're completely removing metastatic cancers by boosting the immune system regularly now.

Just to make you think, when I was 19 I did Sanger sequencing, about a day or 2 of hands-on work for 200 base pairs. Now I'm 39, we have an Illumina Nextseq 500 in our lab, we're sequencing 1200 billion (1.2e11) base pairs in one experiment (assuming 2x150 bp reads, 400 million reads). A Novaseq can do a lot more... Crazy.

Is sequencing 'hard' computational work? Could we use it for proof-of-work?

Aligning all the short reads a (Sequencing By Synthesis) Next Generation Sequencer (to be very specific) produces (hundreds to thousands of millions) to a reference genome is hard computational work indeed, no idea if you can use it for proof-of-work but I like where this is going... But do you not need some kind of definition of correct (like hash needs many leading 0's) for PoW? How would that work for aligning reads to a reference genome? Maybe it could, find the position of the read is hard (I mean, not really for a modern CPU but relatively... I think... not an expert on that), verifying how correct it is, is not hard (I think). Maybe we should ask the BWA devs [0].

[0]: https://github.com/lh3/bwa

I’d be in line to purchase some HengCoin. It’s an interesting idea but you also raise a good point that alignment is probabilistic.

It is the step that most benefits from cpu parallelization so would be cool to explore at least

What do you mean by alignment being probabilistic? If you mean that some reads align faster and you could game the system, then perhaps we should tie the system to hospital based verification of the input data.

Ie, hospital publishes sequencing data (perhaps using fully homomorphic encryption to keep this very sensitive data private), someone aligns it, someone (or the hospital) verifies it, aligner gets paid coin.

The verification of the alignment being easier than the alignment itself is analogous to blockchain verification being easier than actually signing a block, right?

Not quite the best phrase I'll admit. It's identifying the best fit. That's not the same as identifying truth. For instance, my recollection is that bwa-mem has (had?) some small amount of nondeterminism in it.

Ah yes, it would be easy to confirm a good alignment, identifying if any alignment is the best there is would be more difficult I guess, indeed.

RNA can do much of what proteins can do and much of what DNA can do, albeit not so well. It's plausible that early life was an "RNA world" before proteins and DNA.

Don’t we have an advantage in studying RNA (or “junk” DNA) over proteins in that sequencing of nucleic acids is far easier than sequencing of proteins? Seems fortuitous for our research efforts that these nucleic acids play a bigger role in biology than we initially thought.

Sequencing nucleic acids (RNA, DNA) is more straightforward, though protein sequencing tech is fairly functional too, if more expensive and complicated, machinery wise.

There are some recent startups (Glyphic Bio out of MIT, and Jonathan Rothberg's Quantum-Si) that are tackling next-gen protein sequencing. I'm eager to see what they can do once they're widely available.

I’m particularly excited about nanopore protein sequencing. I don’t think there are any startups yet but the technology is commercially available for DNA sequencing.

There’s some very recent progress in the area!

“Multiple rereads of single proteins at single–amino acid resolution using nanopores”: https://www.science.org/doi/10.1126/science.abl4381

(Unfortunately paywalled, but the senior author explained the paper in a Twitter thread: https://twitter.com/cees_dekker/status/1456323490647212033)

You’re correct that sequencing RNA/DNA is currently much cheaper and easier than directly sequencing proteins in a cell.

But, knowing the sequence of a biomolecule is only a first step in understanding it’s function. By-and-large, we’ve had significantly more progress in describing functional domains (and therefore tying them to important biological processes) in proteins than we have in RNA.

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