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    If there are any questions or remarks, I am right here!

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      I wish I could invite this story multiple times. The perfect combination of being approachable, while still being packed with (to me) new information. Readable without ever being condescending.

      One thing I learned was that DNA printers are a thing nowadays. I had no idea. Are these likely to be used in any way by amateur hackers, in the sense that home fusion kits are fun and educational, while never being useful as an actual energy source?

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        So you can actually paste a bit of DNA on a website and they’ll print it for you. They ship it out by mail in a vial. Where is breaks down is that before you inject anything into a human being.. you need to be super duper extra totally careful. And that doesn’t come from the home printer. It needs labs with skilled technicians.

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          Could any regular person make themselves completely fluorescent using this method? Asking for a friend.

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          You may be interested in this video: https://www.youtube.com/watch?v=2hf9yN-oBV4 Someone modified the DNA of some yeast to produce spider silk. The whole thing is super interesting (if slightly nightmarish at times if you’re not a fan of spiders).

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            So that’s going to be the next bioapocalypse then. Autofermentation but where as well as getting drunk, you also poop spider silk.

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          Love the article. Well done.

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            Thanks for the awesome article! Are there any specific textbooks or courses you’d recommend to build context on this?

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              Not really - I own a small stack of biology books that all cover DNA, but they cover it as part of molecular biology, which is a huge field. At first I was frustrated about this, but DNA is not a standalone thing. You do have to get the biology as well. If you want to get one book, it would have to be the epic Molecular Biology of the Cell. It is pure awesome.

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                You can start with molecular biology and then a quick study of bio-informatics should be enough to get you started.

                If you need a book, I propose this one, it is very well written IMO and covers all this stuff.

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                Great article! I just have one question. I am curious why this current mRNA vaccine requires two “payloads” ? Is this because it’s so new and we haven’t perfected a single shot or some other reason?

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                  As I understand it[1] a shot of mRNA is like a blast of UDP messages from the Ethernet port — they’re ephemeral and at-most-once delivery. The messages themselves don’t get replicated, but the learnt immune response does permeate the rest of the body. The second blast of messages (1) ensures that the messages weren’t missed and (2) acts as a “second training seminar”, refreshing the immune system’s memory.

                  [1] I’m just going off @ahu’s other blogs that I’ve read in the last 24 hours and other tidbits I’ve picked up over the last 2 weeks, so this explanation is probably wrong.

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                    It’s just the way two current mRNA vaccines were formulated, but trials showed that a single shot also works. We now know that two shots are not required.

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                      The creators of the vaccine say it differently here: https://overcast.fm/+m_rp4MLQ0 If I remember correctly, they claim that one shot protects you but doesn’t prevent you to be infective, while the second make sure that you don’t infect others

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                      Not an expert either, but I think this is linked to the immune system response, like some other vaccines, the system starts to forget, so you need to remind him what the threat was.

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                      Is there any information on pseudouridine and tests on virus encorporating it in their DNA?

                      The one reference in your post said that there is no machinery in cells to produce it, but the wiki page on it says that it is used extensively in the cell outside of the nucleus.

                      It seems incredibly foolhardy to send out billions of doses of the vaccine without running extensive tests since naively any virus that mutated to use it would make any disease we have encountered so far seem benign.

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                        From https://en.wikipedia.org/wiki/Pseudouridine#Pseudouridine_synthase_proteins:

                        Pseudouridine are RNA modifications that are done post-transcription, so after the RNA is formed.

                        That seems to mean (to me, who is not a biologist) that a virus would have to grow the ability to do/induce such a post-processing step. Merely adding Ψ to sequences doesn’t provide a virus with a template to accelerate such a mutation.

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                          And were this merely a nuclear reactor or adding cyanide to drinking water I’d agree. But ‘I’m sure it will be fine bro’ is how we started a few hundred environmental disasters that make Chernobyl look not too bad.

                          ‘We don’t have any evidence because it’s obvious so we didn’t look’ does not fill me with confidence given our track record with biology to date.

                          Something like pumping rats with pseudouridine up to their gills then infecting them with rat hiv for a few dozen generations and measuring if any of the virus starts encorporating pseudouridine in its RNA would be the minimum study I’d start considering as proof that this is not something that can happen in the wild.

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                            As I mentioned, I’m not a biologist. For all I know they did that experiment years ago already. Since multiple laymen on this forum came up with that concern within a few minutes of reading the article, I fully expect biologists to be aware of the issue, too.

                            That said, in a way we have that experiment already going on continuously: quickly evolving viruses (such as influenza) that mess with the human body for generations. Apparently they encountered pseudouridine regularly (and were probably at times exposed to PUS1-5 and friends that might have swapped out an U for a Ψ in a virus accidentally) but still didn’t incorporate it into their structure despite the presumed improvement to their fitness (while eventually leading our immune system to incorporate a response to that).

                            Which leaves me to the conclusion that

                            1. I’d have to dig much deeper to figure out a comprehensive answer, or
                            2. I’ll assume that there’s something in RNA processing that makes it practically impossible for viruses to adopt that “how to evade the immune system” hack on a large scale.

                            Due to lack of time (and a list of things I want to do that already spans 2 or 3 lifetimes) I’ll stick to 2.

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                        I enjoyed the article, reminded me of my days at the university :-)

                        So here are some quick questions in case you have an answer:

                        • Where does the body store info about which proteins are acceptable vs not?
                        • How many records can we store there?
                        • Are records indexed?
                        • How does every cell in the body gets this info?
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                          It is called negative selection. It works like this:

                          1. Body creates lots of white blood cells by random combination. Each cell has random binding sites binding to specific proteins and will attack them.
                          2. Newly created white blood cells are set loose in staging area, which is presumed to be free of threats. All cells triggering alarm in staging area kill themselves.
                          3. White blood cells, negatively selected not to react to itself, mature and are released to production.
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                            Interesting, thanks for sharing!

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                            How does info spread through the body

                            I came across this page relatively recently and it really blew my mind.

                            glucose is cruising around a cell at about 250 miles per hour

                            The reason that binding sites touch one another so frequently is that everything is moving extremely quickly.

                            Rather than bringing things together by design, the body can rely on high-speed stochastic events to find solutions.

                            This seems related, to me, to sanxiyn’s post pointing out ‘random combination’ - the body:

                            • Produces immune cells which each attack a different, random shape.
                            • Destroys those which attack bodily tissues.
                            • Later, makes copies of any which turn out to attack something that was present.

                            This constant, high-speed process can still take a day or two to come up with a shape that’ll attack whatever cold you’ve caught this week - but once it does, that shape will be copied all over the place.

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                              I did some projects in grad school with simulating the immune system to model disease. Honestly we never got great results because a lot of the key parameters are basically unknown or poorly characterized, so you can get any answer you want by tweaking them. Overall it’s less well understood than genetics, because you can’t study the immune system in a petri dish. It’s completely fascinating stuff though: evolution built a far better antivirus system for organisms than we could ever build for computers.

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                            This was a super interesting read, thanks!

                            I’m particularly impressed that you managed to explain this in such a way that it could be understood by me, an idiot in this field. I suspect I’ll be coming back to it with a highlighter to go off and do some more in-depth reading, but I didn’t feel I missed anything.

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                              Amazing article, thank you @ahu

                              A few questions, if I may — and please understand that I don’t even know what I don’t know about this sort of thing, so forgive me if these are stupid or silly questions.

                              1. If we’re modifying our own cells to make the spike proteins, how do we stop all our cells from getting modified? Do the modified cells not replicate? Is the mRNA “used up?”

                              2. With the advent of these technologies, are we basically able to create vaccines on demand very rapidly, or are these techniques only applicable to SARS-CoV-like viruses (not that that isn’t enough!)?

                              3. Did previous vaccines modify our existing cells like this, or is this new to the mRNA technique?

                              4. Replacing U with psi makes our immune system ignore the protein. Is there any chance evolution will give us a virus with U replaced with psi in nature, making a virus that is just completely ignored by our immune system? That seems like it would be bad.

                              And finally, I am not a religious man, but…I definitely have a sense of wonder looking at how DNA and RNA work and encode information, and I am in absolute awe at what humankind can do now. As someone said, we’re halfway between apes and God and seem to be heading in the right direction…

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                                1: Yes, explicitly. The mRNA is “one shot”, and it degrades quickly. By design. 2: Yes and no. This technology has been tried against influenza for example, but that is a very very clever virus. But it appears that mRNA will be extremely useful for coming to the universal flu vaccine. And even if we can’t do the universal one, we could quickly print the most useful one for.. this month :-) 3: Previous vaccines injected dead or living or modified existing viruses. Some of these did the very same thing - get our cells to build proteins. That part is not new. It is just a lot more surgical now. 4: Good point, but there is happy news. The whole “architecture of life” can’t make these psi things. And viruses ride that architecture. This needs a lab.

                                And yes, I am not religious either but the sheer sense of AWE can be overwhelming!

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                                  May I double-check my understanding of #4 with you? Biology is not my field but the way I think of it is that cells and organisms are basically factories for assembling/moving around/ripping apart chunks of molecules, of various types. So it sounds like this Ψ faux-RNA sequence is a piece of molecule that never appears in any living organism, but is the right shape that it slots into the “build protein” machinery and tells it to make the same thing that a U would in its place. But if you feed that RNA sequence it into the cell’s “copy DNA/RNA” machinery then it doesn’t work, because the molecular machinery doesn’t know how to handle it, and because there’s no molecular machinery in any living organism for manufacturing the Ψ piece-of-molecule and bringing it to the right place. So to teach a cell how to handle a Ψ in its genetic sequence you’d have to make a whole metabolism that could build it, tear it apart, and get it to the right places in the right amounts. Am I understanding this properly?

                                  Pretty cool, if so. Basically sounds like genetic ROM.

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                                    You got that right. To change this is definitely a forklift operation :-)

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                                    Could someone artificially enhance an existing virus by replacing U with Ψ as some sort of biological warfare?

                                    Edit: Also, thank you for making this so understandable! This was probably the best thing I’ve read all year.

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                                    For a sense of scale on #2 at least… they mention in the article that they had to make some alterations to the protein the cell synthesizes this way to make it actually work properly and not just fold up into a mess. These alterations were based on research that other people did in 2017 on similar viruses in the family. So even if it’s “easy” to use this technology to tell cells to make new things, there’s more than a little finesse in making things that do what you want.

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                                    Thank you for the article! What a fascinating read, and you made it so digestible.

                                    The part I had the hardest understanding was the video from Wikipedia. I feel like I almost get it, but I just want to know even more nitty gritty details, like what are each of those colored things? How do they get there? Why are they being locked into place onto the ribbon? How do they get off the ribbon? How is the machine formed in the first place? It’s so fascinating, but the more details I’m given, it seems to prompt even more questions.

                                    I couldn’t help but wonder what kinds of nefarious things could be done with that Ψ trick. It seems like this is just a silver bullet to make intentional viruses infect humans that completely evade our immune systems?

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                                      So the flying things are explained in the video on https://berthub.eu/dna/ - and I think your question about the Ψ-trick might be addressed by some of the other answers on this page.

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                                        Thanks for the tip, I ended up purchasing Molecular Biology of the Cell, can’t wait to read it!

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                                        The Ψ thing (that I was wondering about as well) discussed elsewhere was “Could nature figure out Ψ organically and thereby evolve viruses that evade our immune system?” and thankfully the answer is a resounding “No” (unless the entire mechanism including ribosomes learns how to create those things, I suppose, by which point the immune system probably catches up as well?)

                                        It’s not explicitly spelled out, but as I understand it, this also means that an artificially created/modified virus that comes with Ψ to evade the immune system couldn’t make our cells create Ψ. So either such a virus would be replicated with U in place of Ψ (if the functional equivalence extends to the replication) or the replication would fail entirely (because Ψ is an invalid input to the full replicator pipeline), I’m not sure.

                                        Either way, the best outcome for such a virus (it’s replicated with U) would be that it can create a larger starter colony inside the organism of the first infected victim but any follow-on generations, including those transmitted to other individuals are fully visible to the immune system.

                                        (disclaimer: lots of conjecture)

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                                        Awesome article, thanks. By the way,

                                        In addition, there is a clever lipid (fatty) packaging system that gets the mRNA into our cells

                                        Any chances of expanding on this subject a little bit? How exactly it enters the cell? Could you share some approachable papers/articles about it?

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                                          Sadly i don’t understand a lot of that part. But other people do, I’ve been trying to get Derek Lowe to do a writeup. But he’s also busy.

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                                          Over many years of experimentation, it was found that if the U in RNA is replaced by a slightly modified molecule, our immune system loses interest.

                                          I feel as if I have no right to call myself a hacker while people in our time discover hacks as good as this.

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                                            Thank you for this article and for embracing people’s follow-up questions here 🙂. I learned so much.

                                            This feat and all that has gone into it (that I can’t even begin to fully comprehend) is incredible. I’m floored by what the world has pulled off this year. Amazed and thankful.

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                                              It’s like alien technology, millions of years old.

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                                                Loved the article. This is a realm of science that usually is quite impenetrable for newbies, but I learned a lot with both the article and the answers you gave here. Thanks @ahu!