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A representative idea: if you are the one to kill a deer to eat, you get a little bit of each cut - rib, loin, filet, heart, etc. When was the last time most people ate a filet mignon?

And if you gather food like berries and fruits - you (at least sometimes) get to eat foods ripened that day in the field. How many today get that luxury?

And if one of the things that provides joy to humans is to prepare their family’s food - many folks today would be disqualified.


Yep - cells would die. ...UNTIL they accrue enough dna damage to accidentally either:

- create a new way to generate thymidine

- fall into a proliferation strategy that no longer needs thymidine

Human cells did the same thing and created checkpoints to preclude malignant growth. There are a number of checkpoints already employed in your own bodies. But if you accrue enough DNA damage, you can get around each of those checkpoints (and get cancer):

- IF too much DNA damage, then die

- IF divided too many times, then die

- IF committed to die, actually die

But if a cell collects enough damage, it can get around ALL of the checkpoints. And evolution has shown us that there is no perfect watcher of the watchmen. Still pretty cool to create a new checkpoint this way.


If I was in an environment where such strong mutations can happen in a single generation of non-reproducing cells, I'd ve very worried about the health of my original cells.


What about the heterogeneity of the original cells?


If the DNA is in the cell's nucleus, the DNA will be utilized to produce whatever gene is encoded in the DNA. But if the DNA is just floating around on its own it will not survive a cell division event and the material would need to be periodically reinjected to keep working. However, if the injected DNA is part of a full chromosome, it will be replicated when the cell divides - and will be permanent as long as the cell or its progeny survive.

Some viruses will just inject the DNA into cells, but will not become part of the cell's genome ("transient" transduction). Other viruses (like lentiviruses and these adeno-associated viruses [AAVs]) inject their DNA not just into the cells, but also have machinery that splices their payload DNA directly into the cell's chromosomes ("integrated"). The location in the genome of the splicing event is relatively random. Random is not necessarily great as it could interrupt other genes already in the chromosome. CRISPR is a now-famous tool that helps "integrate" DNA into a specific spot in the genome by being guided to a specific location with a small piece of a specific sequence.

Once the DNA is integrated, any cell, and any of the cell's progeny, will produce or "express" the gene on the delivered DNA. In this case, they delivered the 5991 characters of DNA associated with the OROF gene [1].

[1] https://en.wikipedia.org/wiki/Otoferlin


This is actually not totally correct. AAV’s form episomes, which are circular DNA structures that are basically extra chromosomes. The fact that AAV’s don’t randomly insert themselves into DNA makes them safer for clinical uses like this.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519600/


And that’s why replies are helpful in these kind of explanations. My over-edits became wrong, and then an hour later, unfixable. bglazer is correct.

AAVs, unlike Lentiviruses, do NOT integrate.


The reason I know this is I made the same mistake in a comment on a similar story a few weeks ago!


Thank you for this description of how it works. It seems like truly beautiful and terrifying magic.


Timestamp in the videos: 21:03-4:33 => 7.5hrs


There’s one law of physics difference here: (with a few exceptions) helium, because it’s lighter than air, will never replenish on our planet. There is currently most of what there ever will be. Unlike (almost?) every other object of commerce, there is an almost completely inelastic total supply. It is the ultimate non-renewable resource.


and youtube video of the 'reveal':

https://www.youtube.com/watch?v=n--zawliqvA


Indianapolis was too fast and hot that one year, one of the (two) tire manufactures disqualified their tires (and teams). So not even half the field ran the race. The Indy 500 course has a half-mile straightaway which allowed the F1 cars to build up unprecedented speed - all in hot midwestern summer heat.

Seems the diligence on local weather is not so good with these folks...

[*] "Michelin's tyre mistake sends US Formula One Grand Prix into farce" https://en.wikinews.org/wiki/Michelin%27s_tyre_mistake_sends...


Yeah, that was absurd too.


Snowden also brought the goods (actual docs) so that the existing cases and inquiries could proceed without getting the Glomar response - “cannot answer the question of whether you have standing, as we can neither confirm nor deny the program either exists.”

And this was deliberate. Those in the know knew _of_ the program, but could do little actionable with that knowledge without Snowden’s public proof.


You (at least) have 3 systems that are optimized in concert in a (our) DNA/Protein world.

DNA base set, Amino acid set, Translation layer between DNA/Proteins.

Currently, we've got: 4 DNA bases, 3 bases/AA, 20 AAs; 4^3 => 20

If you change one of those numbers, you'll need to rejigger the rest, and you'd need to reoptimize. And there are competing goals which at least include: - maximize access to biophysical/chemical diversity - minimize energy expenditure to produce each component, chemically - minimize energy expenditure to both copy instructions & produce products - maximize information fidelity - minimize or at least degrade gracefully in the context of errors

In the context of a 3-base system, you very well could throw off those optimizations given the consequences for the other 2 parameters (#AA & nt/AA). 3^3 = 27, which is very close to the maximum of 20 amino acids. Which means you'd probably need a 4nt->AA translation layer to keep the same number of AAs, and that alone would add 30% more energy expenditure. If you kept the 3nt->AA system you'd BOTH need to reduce the number of accessible amino acids AND you'd lose some of the error correction mechanisms of having degenerate codons code for the same amino acid.


BUT, if you look at the codon table, precisely because it's base-4 and not base-3, many base flips are silent when coded.

By using base-4, there's enough space to permit lossiness of the coding itself - given the number of amino acids and the 3-NT encoding.

So you really aren't optimizing JUST for nucleotide encoding, but you're also optimizing in concert with 3-nt/AA, and 20AA codes.

So if you have to optimize for information density and fidelity, given X-nucleotides, Y nucleotides/AA, and Z AAs, and sample as much chemical and physical diversity in those AAs life has settled upon: X=4, Y=3, Z=20.

If we went with X=3, you might need Y=4 to get the same kind of fidelity, but that cranks up your energy costs by 30% (from 3 to 4 NT per AA).


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