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One other fun part of gene editing in vivo is that we don't actually use GACU (T in DNA). It turns out that if you use Pseudouridine (Ψ) instead of uridine (U)
by Balgair 1y ago
One other fun part of gene editing in vivo is that we don't actually use GACU (T in DNA). It turns out that if you use Pseudouridine (Ψ) instead of uridine (U) then the body's immune system doesn't nearly alarm as much, as it doesn't really see that mRNA as quite so dangerous. But, the RNA -> Protein equipment will just make protiens it without any problems.
Which, yeah, that's a miraculous discovery. And it was well worth the 2023 Nobel in Medicine.
Like, the whole system for gene editing in vivo that we've developed is just crazy little discovery after crazy little discovery. It's all sooooo freakin' cool.
https://en.wikipedia.org/wiki/Pseudouridine https://en.wikipedia.org/wiki/Pseudouridine
- Teever 1y agoI suppose a downside (depending on your perspective) of this is that it will make people who are genetically modified in this fashion trivial to detect. That's good if your goals are to detect genetic modification which may be considered cheating in competitive sports. That's bad if your goals are to detect genetically modified people and discriminate against them. I see a near future where the kind of people who loathe things like vaccines and genuinely believe that vaccines can spread illness to the non-vaccinated feel the same way about other things like genetic modification and use legal mechanisms to discriminate and persecute people who are genetically modified.
- ale42 1y ago> it will make people who are genetically modified in this fashion trivial to detect. I'm not totally sure. If I understand it correctly, the mRNA contains pseudouridine, and it makes the protein that will edit the DNA. The edited DNA should look like a normal one.
- Teever 1y agoAh. That makes sense. My mistake.
- LawrenceKerr 1y agoIf you're going to make the comparison with vaccines, and if history is any indication, the more realistic worry would be the other way around (since that's where the money is): that genetic modifications will be mandated, and that those who object will be discriminated against. [And no, I am not anti-vax, nor anti-gene-editing.]
- khazhoux 1y ago“What do you mean you haven’t modified your chromosome 7 CFTR gene? And you’re planning to have children???”
- kulahan 1y agoIt wouldn’t be crazy if I teleported 50 years in the future and heard someone tell me that not doing this is akin to child abuse. Obviously all suffering is relative, etc. etc., but it’s just interesting to imagine a world where the societal pressure to make a perfect child is high.
- _whiteCaps_ 1y agoI don't know anything about gene editing, but my grandmother was a carrier of the BRCA mutation. It would have saved a lot of heartbreak in my family if that could have been detected and repaired. My aunt, mom, and brother (age 4) all died of cancer. I'm just glad that my mom didn't know she had the mutation and passed it on to her child.
- sfink 1y agoCareful with qualifiers there. I genuinely believe that vaccines can spread illness to the non-vaccinated, since it has happened many times and is well-documented. For example, it's why only the inactivated (aka "dead" virus) polio vaccine has been used in the US since 2000. I'm not arguing about whether the risks of the attenuated virus outweigh the benefits. I think the data are very clear there. (Heh -- and I'm sure the vast majority of people will agree with that statement, even if they disagree on what the clear answer is....) It's just that one shouldn't mock a belief without including the necessary qualifiers, as otherwise you're setting up an argument that can be invalidated by being shown to be factually incorrect. As for genetic modification of humans, IMO there are a lot of very good reasons to be wary, most of them social. Fatal hereditary conditions are obviously an easy call. What about autism (not saying there's a genetic link there to use, just a what if)? Or other neurodivergence? Like being a troublemaker in class? Or voting for the party that doesn't control the medical incentive structure? Heck, let's stick with the fatal hereditary conditions, and say the editing does not affect germ cells. Is it ok if the human race gradually becomes dependent on gene editing to produce viable offspring? Or let's say it does extend to germ cells. The population with resources becomes genetically superior (eg in the sense of natural lifespan and lower medical costs) to those without, creating a solid scientific rationale for eugenics. Think of it as redlining carved into our blood. I don't think discrimination against the genetically modified is the only potential problem here. As humans, we'll deal with these problems the way we've dealt with everything else transformational. Namely: very, very badly.
- catigula 1y agoI mean, I feel like autism is a terrible example here, it's not just some quirky personality trait, it's a reality people live with that runs the gamut from difficult to completely debilitating. Even the more mild forms of autism cause extreme difficulty in many aspects of life. If that was curable or preventable, that'd be great. If it turns out some pathogen or chemical made me autistic, regardless of whether or not I could be cured as an adult, I'd have certainly preferred to live the reality where I had been as a child.
- sfink 1y ago
- emseetech 1y agoI'm less interested in detecting genetic modification for the purposes of discrimination than making sure it's available to everyone. Assuming requisite safety of course.
- ddq 1y agoI'm more concerned about the possible negative unintended consequences of making it available to everyone first. Genetic modification is well-explored Pandora's Box in science fiction and present humanity seems so ill-equipped in collective philosophy and reason to handle a paradigm shift of that magnitude.
- jillyboel 1y agoDon't be silly, the rich will want their babies to be perfect so gene editing will be legal and considered OK.
- _bin_ 1y agoCan you explain why this is a bad thing, or is it just “”the rich” bad”?
- jhickok 1y agoNot OP, but presumably it's because it could cement a permanent divide between classes. We still have quite a bit of upward mobility in the US, but health is a tremendous predictor of future outcomes, so gating that to the rich is dangerous to the stability of society in that way.
- _bin_ 1y agoThis seems like more of an issue with accessibility of the treatment than the treatment itself If we could make most children smart, productive, ambitious, courteous, civil, conscientious, honorable, strong... the value to society is probably high enough to justify covering it for almost anyone.
- deleted 1y ago[deleted]
- boroboro4 1y agoThe society already can invest a lot (through public education) to “make most children smart, productive, ambitious …”. Somehow society (or indeed parts of it) decided to use it as a tool of further segregation rather than overall prosperity. I’m afraid same might apply to this.
- _bin_ 1y agoWe "invest" more than almost anyone. 38% higher than the OECD average. I don't find discussions about throwing more money at the problem to be constructive so much as a way to ignore other issues at play. I don't really see how this affects e.g. what I do for my children. I will absolutely be turning them into the closest to superhuman the current state of treatments lets me, traveling internationally if I need to. If someone else decides to segregate access to treatment, that is a separate, wrong act that will not hold me back from giving my children every advantage possible. (Yes, I understand this is a positional arms race, but 1. that doesn't change the individually-optimal outcome, and 2. that doesn't change that society net benefits from it.)
- deleted 1y ago[deleted]
- junon 1y agoRNA is a byproduct, not a "source of truth" in technical terms. The DNA is. DNA is converted to RNA and then executed and then discarded, per my understanding. The DNA is still AGCT.
- alecco 1y ago> [...] then the body's immune system doesn't nearly alarm as much, as it doesn't really see that mRNA as quite so dangerous Please tell me there are measures to prevent this going into the wild. Please tell me this won't be used in large-scale industrial farming.
- imcritic 1y agoFarming? This will be used in warfare.
- Balgair 1y agoNot under the current way we do things, I don't imagine. So the real trick here isn't the mRNA, it's the nanobubbles. Basically, you're putting these bits of mRNA into these little fat bubbles and then injecting those into the blood. Making those bubble shelf stable is really hard, hence the issues with temperature and the covid vaccine. To then make those little fat bubbles stable-ish in the blood is also a really hard thing to do. They have to get to the right places (in this baby's case, the liver) and then degrade there, drop off the mRNA, and not mess up other tissues all that much. Like, it's not terrible to make these micelles degrade in vivo, but to have them do that and not degrade in the tubes, ... wow... that is really difficult. There's a reason that Moderna is so highly valued, and it's these bubbles. To try to then put these in a weapon that could do this though the airways would be, like, nearly impossible. Like, as in I think the second law of thermodynamics, let alone biology, and then simple industrial countermeasure like a N95 respirator, yeah, I think all of that makes it pretty much impossible to weaponize. (Hedging my bets here: I don't know if they had to do all that with this baby, as you can kinda go from lab to baby really fast, since it's such a special case. But for mRNA based vaccines and cancer treatments, you have to deal with the shelf stable issue) (Also, other bio people, yes, I am trying to explain to laymen here. Please chime in and tell me how I'm wrong here)
- okayishdefaults 1y agoI think it doesn't need to be a direct weapon to be used in warfare. You can genetically modify your own military.
- monkeycantype 1y agoI remember from a few few years back that the lipid coating may have caused problems for the liver, when treating people for diseases that needed to target a lot of tissue, such as muscle disorders. Is that still the case?
- Balgair 1y agoUnfortunately, I do not know. Sorry here. If anyone else does know, please chime in!
- mike_hearn 1y agoYou remember correctly. Moderna had a lot of problems with their drug trials due to the lipid nanoparticles they were using to transport mRNA. They were toxic to the liver upon repeat dosings. Unfortunately, it appears they never found a fix for the problem. Instead they gave up and found a "business solution" by pivoting from drugs to the (at the time) less profitable vaccines, on the grounds that vaccines are something you only need to take once so the toxicity issue could be dodged. Doh. That was in 2017. https://www.statnews.com/2017/01/10/moderna-trouble-mrna/ https://www.statnews.com/2017/01/10/moderna-trouble-mrna/ By the time COVID vaccines came around a few years later there was no evidence they had fixed the problems with lipid nanoparticle delivery. I looked for such evidence extensively at the time, for example, announcements by Moderna of breakthroughs or trials of new drugs. Today the situation seems not much different. Note that Moderna's wikipedia article has a section on "rare disease therapeutics" but it's literally empty: https://en.wikipedia.org/wiki/Moderna#Rare_disease_therapeutics https://en.wikipedia.org/wiki/Moderna#Rare_disease_therapeut... Because of their failure to progress beyond COVID vaccines Moderna's share price got slaughtered, falling from a peak of ~$450 to ~$25 today. I don't know if other companies were able to find breakthroughs here, after COVID I stopped following the topic. Unfortunately, although mRNA tech has great potential, when normal safety standards were reimposed it appears that Moderna went back to being unable to make anything safe enough to launch.
- Jugurtha 1y agoWhat was the success of other means, such as sugars and proteins? Something like glycocalyx or polysaccharide capsules? Or HIV like deployment gp41/gp120?
- maxerickson 1y agoIs this a troll? Pseudouridine mRNA isn't gene editing.
- VierScar 1y agoWhat do you mean? Is mRNA not used to produce the enzyme that these comments mentioned? I don't think they were saying mRNA is gene editing itself. Just commenting on a modified mRNA helping the process compared to normal mRNA. Might be misunderstanding though so correct me if I am
- maxerickson 1y agoI dunno, I think they are being sloppy and conflating things. We can induce manufacture of proteins and can design proteins that carry out gene editing, so we can stack that knowledge together to induce cells to manufacture proteins that carry out gene edits, but it's the payload that is the gene editing, not the instruction to make the protein. Given the merry movement to call the COVID vaccines gene editing, it rankles.
- Balgair 1y agoHey, yeah, I'm not the most up to date on the current methods. Most of my knowhow is a bit out of date here. So thanks for piping up to correct things. Do you know of any good resources that I can use to get up to speed on the exact methods they used for the baby? My understanding, outdated as it is, is that we're using the mRNA to go in and create CRISPR-CAS9 slicers/dicers and additionally to that, the correct genes (not mRNA) to get stitched in. I would love to know more about how I am wrong here, as I am sure I'm not even close to really understanding it. Thanks!
- ionwake 1y agoI think you're replying to someone edgelord about covid who got confused about some mrna statement and then back pedalled re-affirming what the article was about.
- 1y ago
- cm2187 1y agoThat also sounds like a recipe for a terrifying virus
- dtpro20 1y agoIt's almost exactly the premise of the movie "I am Legend," But it uses CRISPR instead of a Virus as the delivery mechanism.
- dapf 1y agoIt sounds like Spiderman tech.
- vanderZwan 1y agoI would be surprised if viruses using U instead of T didn't already exist. After all, don't all viruses work by doing gene editing in vivo, except just localized to one cell? EDIT: well, I suppose the question is whether cells of living beings could produce the U required for the viruses. But if not, then a wild virus using U instead of T to bypass our immunity also would not be a threat for that very reason.
- snalty 1y agoIt’s not the use of Uracil/Urimidine that bypasses the immune system. RNA uses Uracil instead of thymine in all organisms afaik, and RNA viruses certainly exist. It’s pseudouridine that’s the magic stuff.
- teekert 1y agoI feel a bit proud that humanity healed a baby with this tech before any viruses were constructed/released.
- Symmetry 1y agoIt would allow a synthetic virus to get a foothold in your cells more easily, but our cells don't make Pseudouridine naturally which throws a big wrench in the ability of a virus to copy itself. And without replication you don't have a serious infection.
- 1y ago
- xkcd1963 1y agoWow that could be also abused by some future covid-lab to bypass immunesystem and modify the DNA so the body disfunctions
- Balgair 1y agoYeah, I mention this in some other comments that got greyed out. Basically, the real deal technology here is the lipid bubbles that deliver the payloads to the right cells, not the base modification. You can go look at them, and a lot of other comments in this thread for more info on that tech. TLDR: No way that anyone can bypass anything. These lipid bubbles are a miracle that they work at all; they're so unstable, it boggles the mind we can even use them to begin with. Doing any large scale DNA editing on an unsuspecting population would be so insanely expensive and difficult, I certain moving to the Moon would be cheaper.