[Balgair]

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

[monkeycantype]

I 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?

[mike_hearn]

You 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/

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_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]

What was the success of other means, such as sugars and proteins? Something like glycocalyx or polysaccharide capsules? Or HIV like deployment gp41/gp120?

[Gareth321]

> on the grounds that vaccines are something you only need to take once so the toxicity issue could be dodged

But we didn't take these vaccines once. We took many of them. Am I to understand a known side effect is liver toxicity for multiple doses?

[popol12]

I guess the issue is not about taking the medicine once vs twice, but rather « a few times » vs « daily »

[Gareth321]

It sure would be nice to see the data on length of time between doses to prevent toxicity. The fact they deleted all of that data sure is suspicious and incredibly worrying.

[mike_hearn]

You have successfully read between the lines, yes.

[Avamander]

They have not.

[heavyset_go]

Toxicity depends on dose. COVID vaccines just need micrograms of material to induce an immune response, I imagine it takes more than that to edit the genes of a large organ.

[mike_hearn]

There have sadly been cases where the vaccines did perform unintended gene editing. It shows up as people whose bodies are still producing spike protein months or years after vaccination.

[floam]

Are you saying that there are cases of longer than expected spike protein presence where these cases are actually because gene editing took place?

[Balgair]

Unfortunately, I do not know. Sorry here.

If anyone else does know, please chime in!

[cm2187]

That also sounds like a recipe for a terrifying virus

[Symmetry]

It 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.

[vanderZwan]

I 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]

It’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]

I feel a bit proud that humanity healed a baby with this tech before any viruses were constructed/released.

[shiandow]

I don't thnk the body has a way of making mRNA with pseudouridine.

[dtpro20]

It's almost exactly the premise of the movie "I am Legend," But it uses CRISPR instead of a Virus as the delivery mechanism.

[dapf]

It sounds like Spiderman tech.

[xkcd1963]

Wow that could be also abused by some future covid-lab to bypass immunesystem and modify the DNA so the body disfunctions

[Balgair]

Yeah, 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.

[maxerickson]

Is this a troll? Pseudouridine mRNA isn't gene editing.

[VierScar]

What 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]

I 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]

Hey, 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]

I 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.

[alecco]

> [...] 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.

[Balgair]

Yeah, it's not a drama.

The reason that the body doesn't alarm as much to Pseudouridine, is that it's not a 'natural' RNA base. Meaning that, for the most part, nature really never uses it and so we haven't evolved to look out for it. Nature uses Uridine and so immune systems have evolved to look out for random bits of RNA in the body that use it and then clean that all up.

It's like if you're looking to clean up legos in you house with a romba that only cleans up legos. And all of a sudden it finds a duplo. It's going to take a hot second to figure out what to do with the duplo. And in that time, you can sneak by and build a duplo fort. (Look, I know this analogy is bad, but it's the best I can come up with on the fly, sorry. If anyone else wnats to come up with a better one, please do!).

The Pseudouridine is used up and degraded very quickly inside the cell, minutes at the very very longest, more like microseconds. It's just part of a messenger (the 'm' in 'mRNA') to tell the cell to do things.

You might see mRNA gene editing in factory farms, but it would just be easier to do germline editing instead and skip spraying animals, plants, and fungi. Why waste the equipment, right?

[kulahan]

I thought the analogy was good. They’re meant to be simple and easy to understand, not perfect representations.

[abracadaniel]

As I understand it, there is nothing in nature that can create it, so the mRNA can never be accidentally replicated. It’s a safety mechanism that prevents escape.

[slashdev]

Why would it be used in farming, you can edit the DNA before fertilization in farming, no need to do anything in vivo.

[treyd]

Industrial farming of what?

[imcritic]

Farming? This will be used in warfare.

[Muromec]

That would be less effective than bio and chemical weapons are. Which are not used because they just suck

[kulahan]

I’m not sure of by “they just suck” you meant to imply that they’re ineffective. If that’s the case, I strongly disagree. They are not used because somehow all countries pretty much agreed they’re way TOO effective and horrific. Nobody wants it used on them, so nobody uses it on anyone else.

I cannot imagine a more effective weapon than an invisible gas that melts you alive, and there are MANY chemical and bio examples of these types of weapons.

[wffurr]

>> They are not used because somehow all countries pretty much agreed they’re way TOO effective and horrific

That’s the story but it doesn’t hold up. Chemical weapons were used as recently as the Syrian civil war. I also think if they were really effective in modern warfare, Russia would have long ago deployed them in Ukraine.

More here: https://acoup.blog/2020/03/20/collections-why-dont-we-use-ch...

[kulahan]

What do you mean “if they were really effective”? We still hand out CBRN gear and train in how to put necessary parts on in seconds, because that’s often how little time you get before you’re permanently incapacitated. Mustard gas alone should prove this, and that’s an OLD chemical weapon.

Nowadays we have riot control agents that can be tailored to demographics, react more violently in the presence of sweat, or contain psychoactive ingredients. Nanoparticle dispersion bypasses common gas masks and clothing protection. Even if you’re completely geared up, they can be engineered to last on surfaces for a long time, or react only in the presence of certain triggers. Imagine thinking you’re safe until someone turns on a certain light bulb and you cook inside your protective gear because you were actually exposed 12 hours earlier in an undetectable manner.

[beeflet]

The ceiling for the destruction caused by biological weapons is far greater than chemical weapons. There is no chemical weapon that can hijack the victim to make more of it.

[Balgair]

Not 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]

I think it doesn't need to be a direct weapon to be used in warfare. You can genetically modify your own military.

[Balgair]

Yeah good point!

Something that a lot of people are unaware of is that US Military is allowed to do this. I forget the exact EO, but it was signed by Clinton and is in the 12333 chain of EOs. Mostly, this is used for the Anthrax vaccine. But, it does give clearance to do other forms of medical experimentation on warfighters.

No, really, I am serious here. This is true. I may have the details a bit off, so sorry there, but they can and do preform medical experiments on people without their consent. Now, to be fair, France does this too. They do sham surgeries over there. Non-consenting human medical experimentation is quite the rabbit-hole.

So, I can kinda see in the next 10 years, certainly the next 50, a routine shot given to warfighters to help them with things like blood loss, or vitamin C production, or fast twitch muscles, or whatever. The legal framework is already there and has been for a while, it's just an efficacy issue, honestly.

[Teever]

I 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]

> 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]

Ah. That makes sense. My mistake.

[emseetech]

I'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]

I'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.

[junon]

RNA 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.

[jillyboel]

Don't be silly, the rich will want their babies to be perfect so gene editing will be legal and considered OK.

[_bin_]

Can you explain why this is a bad thing, or is it just “”the rich” bad”?

[jhickok]

Not 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_]

This 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.

[boroboro4]

The 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.

[concordDance]

This is already true to a great extent. A family with lots of genetic health conditions are probably going to remain poor.

[jillyboel]

I'm explaining that gene modification will not be considered illegal or bad because the rich will have a vested interest in it being legal. This is a reply to GP saying:

> use legal mechanisms to discriminate and persecute people who are genetically modified

I believe there is no way this will happen, because legal mechanisms are driven by the whims of the rich, and they will want gene editing to be legal. So there will beno legal mechanisms to discriminate against those who have been edited.

[LawrenceKerr]

If 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]

“What do you mean you haven’t modified your chromosome 7 CFTR gene? And you’re planning to have children???”

[_whiteCaps_]

I 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.

[kulahan]

It 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.

[sfink]

Careful 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.

[nuc1e0n]

At one time organ transplants were considered an ethical grey area (perhaps they still are by some), but I think most people now would consider it better to save lives in such a manner when it only brings help to those who need it and it's possible to, compared to the alternative. Having the capability may mean that things like organ theft now exist, but the benefits around the world outweigh the nastiness that has always come as part of human nature.

[sfink]

I agree that organ transplants are a net positive, and in fact are far less susceptible to unintended consequences (there's a pretty low limit to the number of organs and operations involved, for one.)

I also think that gene repair is a net positive. I would just like us to, for once, look ahead and foresee some of the foreseeable consequences and act to mitigate them before the bulk of the damage is done.

I don't think it's necessary to slow the development; gene therapy is too desperately needed, and slowing it down so that we can prepare is not going to cause us to prepare.

[catigula]

I 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.

[zmmmmm]

I think a better reason autism is a bad example is that part of its definition is that it is a consequence of fundamental brain structure and development (differentiating it from other psychological disorders which are acquired and more malleable). These aren't things you will "undo" with some gene edits. The whole brain has developed in a different way. Short of re-growing them a new brain you aren't going to change that (assuming you wanted to).

[kulahan]

I think scientists have believed for a while that any type of “autism cure” would need to be extremely early intervention for maximum effectiveness for exactly this reason. I remember speaking with a team that was studying detection of autism in the womb for this exact reason.

[sfink]

Sure, the purpose was to illustrate a slippery slope, and curing autism is meant to be more obviously good than abolishing all forms of neurodivergence but less obviously good than fixing fatal hereditary diseases.

I'm not going to claim that I know the perfect place to draw the line.

[mr_toad]

> vaccines can spread illness to the non-vaccinated, since it has happened many times and is well-documented

Nothing in medicine is certain. Nearly any medical treatment has a small chance it could kill you. There’s a small, but non-zero chance of a lethal infection even if they injected you with saline, odds that rise dramatically in less than sanitary conditions.

Ironically the use of the attenuated oral vaccine for polio was because of the risk of infection in places where the availability of sterile syringes was hard to guarantee. It’s all about the relative odds.

[jcims]

>...and say the editing does not affect germ cells.

To me the wildest scenarios take this off the table.