thanks for this, I think all these lay articles on biomedical news should definitely be accompanied by the paper
bookofjoe · 31d ago
I always try but way more often than not the paper is paywalled.
n3uman · 31d ago
One of the authors: Julia L Hacker
MrZander · 31d ago
> To accomplish that feat, the treatment is wrapped in fatty lipid molecules to protect it from degradation in the blood on its way to the liver, where the edit will be made. Inside the lipids are instructions that command the cells to produce an enzyme that edits the gene. They also carry a molecular GPS — CRISPR — which was altered to crawl along a person’s DNA until it finds the exact DNA letter that needs to be changed.
That is one of the most incredible things I have ever read.
Balgair · 31d 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.
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 · 31d ago
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.
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:
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 · 30d ago
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 · 30d ago
> 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 · 30d ago
I guess the issue is not about taking the medicine once vs twice, but rather « a few times » vs « daily »
Gareth321 · 30d ago
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 · 30d ago
You have successfully read between the lines, yes.
Avamander · 30d ago
They have not.
heavyset_go · 30d ago
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 · 29d ago
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 · 29d ago
Are you saying that there are cases of longer than expected spike protein presence where these cases are actually because gene editing took place?
mike_hearn · 29d ago
The Yale LISTEN study found such people for example. Studies on post vaccination heart damage also found free spike protein in the blood of those affected, i.e. the body had turned off the immune response to the spike due to persistent internal production. The most likely way this happened is understood if you dig into it.
karagenit · 28d ago
Do you have a citation for this? The only relevant study I saw on the LISTEN website was a preprint of a study showing data on self-reported post-vaccine symptoms, but didn’t really talk about causes or gene edits (Krumholz et al. 2023).
mike_hearn · 28d ago
It did discuss causes to some surface level: continuous spike protein production, T-cell exhaustion and Epstein-Barr reactivation. And they're investigating post-vaccine syndrome so the root cause there would be clear, as the study authors discussed in the LISTEN press release.
It's easy to find papers discussing the problem, just search Google Scholar. Example:
"Of the S1 positive post-vaccination patients, we demonstrated by liquid chromatography/ mass spectrometry that these CD16+ cells from post-vaccination patients from all 4 vaccine manufacturers contained S1, S1 mutant and S2 peptide sequences"
They can tell the difference between vaccine spike and virus spike as the vaccine spike was modified for stability. The exact pathway is speculated to have been DNA contamination due to manufacturing process defects. Sequencing of vaccine vials has shown far higher levels of DNA contamination than is considered safe, and the lipids would bring DNA into the cells just as well as they do mRNA making the safe levels much lower still.
> A significant limitation of this study was the lack of approved testing to 100% rule out previous
infection and it is possible the persistent S1 protein detected in the CD16+ monocytes of some of
the patients in this study is from SARS-CoV-2 and not from the vaccine. There also exists the
possibility that some of these new-onset symptoms post-COVID vaccination are unrelated to the
vaccines. The data from this study also cannot make any inferences on epidemiology and
prevalence for persistent post-vaccine symptoms. Thus, further studies and research need to be
done to understand the risk factors, likelihood and prevalence of these symptoms.
That also sounds like a recipe for a terrifying virus
Symmetry · 30d ago
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 · 31d ago
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 · 31d ago
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 · 31d ago
I feel a bit proud that humanity healed a baby with this tech before any viruses were constructed/released.
shiandow · 30d ago
I don't thnk the body has a way of making mRNA with pseudouridine.
dtpro20 · 31d ago
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 · 31d ago
It sounds like Spiderman tech.
xkcd1963 · 30d ago
Wow that could be also abused by some future covid-lab to bypass immunesystem and modify the DNA so the body disfunctions
Balgair · 29d ago
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 · 31d ago
Is this a troll? Pseudouridine mRNA isn't gene editing.
VierScar · 31d ago
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 · 31d ago
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 · 31d ago
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 · 31d ago
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 · 31d 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.
Balgair · 31d ago
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 · 31d ago
I thought the analogy was good. They’re meant to be simple and easy to understand, not perfect representations.
abracadaniel · 31d ago
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 · 31d ago
Why would it be used in farming, you can edit the DNA before fertilization in farming, no need to do anything in vivo.
treyd · 31d ago
Industrial farming of what?
imcritic · 31d ago
Farming? This will be used in warfare.
Muromec · 31d ago
That would be less effective than bio and chemical weapons are. Which are not used because they just suck
kulahan · 31d ago
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 · 31d ago
>> 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.
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.
wffurr · 30d ago
I'd encourage you to read the article. Chemical weapons are effectively useless against a well-trained "modern system" army. Part of that is the chemical warfare equipment and vehicles, but mostly it's cover-and-concealment. If you can actually find the enemy, it's much faster and simpler to use the other vastly destructive munitions that modern militaries have.
kulahan · 30d ago
I did, and it’s really not very convincing at all. It uses an example where a terror group in Japan was able to injure thousands of people with a chemical attack, and act as if this is… not a particularly effective outcome?
Additionally, that “if you can find them” is doing some pretty heavy lifting. The range of explosives and kinetics is hilariously low, and the actual percentage of your military with the level of mobility he seems to be referring to is infinitesimal.
This argument more correctly explains why chemical weapons aren’t a great defense against precision strike groups. It also doesn’t get into detail with concepts like dropping a bomb right in the middle of a firefight knowing it literally cannot harm your own troops, short of the physical metal accidentally falling on one of your own troops.
Muromec · 28d ago
>I did, and it’s really not very convincing at all. It uses an example where a terror group in Japan was able to injure thousands of people with a chemical attack, and act as if this is… not a particularly effective outcome?
Yes, it isn't effective outcome in terms of meeting their objective
> It also doesn’t get into detail with concepts like dropping a bomb right in the middle of a firefight knowing it literally cannot harm your own troops
That's a video games logic, it doesn't work like that in practice. Even civil grade riot control tear gas grenade is pretty traumatic because it still explodes to disperse the gas (source : implied first hand knowledge). That and warfare is messy, which means half the time half the protective gear will be destroyed from the usual exploding and shooting happening, gas gets carried away by the wind in a random direction, etc, etc.
kulahan · 28d ago
> That's a video games logic
No, it’s science. There are about a million ways to protect your own troops if that’s actually what you want to do.
It feels like you’re arguing against the idea of chemical weapons from the 1940s, rather than nearly a century later.
You don’t need protective gear. You can create sprays, lotions, inhalants, and other countermeasures that don’t stop working the second a piece of cloth rips. Shit, You could make a biological agent that avoids a DNA marker created with an mRNA vaccine. Likely not nearly as fast, but perfectly lethal.
Modern chemical weapons and biological weapons are absolutely incomparable to their Vietnam counterparts.
wffurr · 29d ago
>> a terror group in Japan was able to injure thousands of people with a chemical attack
A terror attack on civilians is a lot different than modern militaries using them on each other.
beeflet · 31d ago
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 · 31d ago
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 · 31d ago
I think it doesn't need to be a direct weapon to be used in warfare. You can genetically modify your own military.
Balgair · 31d ago
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 · 31d ago
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 · 31d 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 · 31d ago
Ah. That makes sense. My mistake.
prisenco · 31d ago
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 · 31d ago
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 · 31d ago
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 · 31d ago
Don't be silly, the rich will want their babies to be perfect so gene editing will be legal and considered OK.
_bin_ · 31d ago
Can you explain why this is a bad thing, or is it just “”the rich” bad”?
jhickok · 31d ago
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_ · 31d ago
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 · 30d ago
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.
_bin_ · 30d ago
We "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.)
boroboro4 · 30d ago
I don't mean to invest as to spend more money, rather to spend money better and in a more equal way. While USA spends a lot of money on education I don't think it translates in better education on average. Even if this was beneficial for the society in general.
I am, afraid, that this kind of genome modification will further increase divide in a society and turn social lifts off even more. I.e. it's not gonna be your kid to get "improve" brain genes first, and later your kid wouldn't get a chance to get it ever again for their children.
Just to be clear I'm not against of the progress, this thing is fascinating and really shows how awesome humans are. And I get why you'll get it if possible for your kid. I'm just not sure its benefits for the society mean it's gonna be anyhow affordable for regular people.
_bin_ · 30d ago
You will have a really hard time convincing Americans to keep paying high taxes while funding is pulled from their children’s schools and redistributed to inner cities and ruralia. My observations suggest the problem for the latter isn’t financial.
concordDance · 31d ago
This is already true to a great extent. A family with lots of genetic health conditions are probably going to remain poor.
jillyboel · 30d ago
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 · 31d ago
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 · 31d ago
“What do you mean you haven’t modified your chromosome 7 CFTR gene? And you’re planning to have children???”
_whiteCaps_ · 31d ago
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 · 31d ago
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 · 31d ago
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 · 31d ago
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 · 30d ago
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 · 31d ago
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 · 31d ago
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 · 31d ago
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 · 31d ago
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 · 31d ago
> 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 · 31d ago
>...and say the editing does not affect germ cells.
To me the wildest scenarios take this off the table.
shadowgovt · 31d ago
Gene therapies are pretty incredible. Some of them are still making a button-hole with a machete, but that's relative to the previous medical intervention of a button-hole with a tank's main gun.
One of the treatments for sickle-cell involves switching off the gene that makes the malfunctioning red blood cells, but of course that's not sufficient; you'd stop making red blood cells completely and you'd die. So it's combined with a modification that switches on a gene that all humans express pre-birth that causes your body to make "super-blood": red blood cells with significantly more binding points for oxygen. This is necessary because a fetus gets oxygen from its mother's blood, so the increased binding affinity is useful for pulling the oxygen towards the fetus at the placental interface. After birth, expression of that gene is disabled and regular RBC genes switch on.
So the therapy doesn't "fix" sickle RBCs; it disables the body's ability to make them and re-enables fetal RBCs! I have seen no literature on whether having fetal RBCs in adulthood has any benefits or drawbacks (besides changing the affinity ratio for their fetus if the patient gets pregnant, I imagine increased-affinity RBC could help for athletics... But I also imagine it requires more iron to generate them so has dietary impact).
nomadpenguin · 31d ago
High affinity RBCs would actually be a disadvantage for athletics. You actually don't need very high affinity to pick up oxygen from the lungs -- your lungs are comparatively extremely high in oxygen. What matters more is being able to drop the oxygen off in peripheral tissues. Higher affinity means that it's harder to actually deliver the oxygen, which is why we evolutionarily developed the switch away from fetal hemoglobin.
philsnow · 30d ago
I thought the evolutionary impetus for fetal hemoglobin was because it greatly increases the efficiency of fetal oxygen uptake across the placental interface?
From shadowgovt:
> I have seen no literature on whether having fetal RBCs in adulthood has any benefits or drawbacks (besides changing the affinity ratio for their fetus if the patient gets pregnant
This was exactly the question that popped into my mind when I read about switching from normal adult RBCs to fetal RBCs: does this therapy reduce the likelihood of carrying a baby to term?
nomadpenguin · 30d ago
Yes, that is true. I phrased that badly -- it's more that we didn't take the evolutionary branch where we retain the fetal hemoglobin because it is maladaptive in adults.
anon291 · 31d ago
I have natural persistence of fetal hemoglobin which counteracts my inherited thalassemia trait.
No problems really..never knew I had it until I was told I had thalassemia trait as part of genetic testing. My hemoglobin panel shows fetal hemoglobin.
j45 · 31d ago
Appreciate the explanations and the analogies.
ziofill · 31d ago
A chemist friend of mine did his thesis on lipid vesicles, and I remember my mind being blown when he told me these are modelled as a liquid on the 2D plane of the membrane, but as a solid on the 1D orthogonal direction because the energy to swap two lipid molecules side by side is incredibly low (because it makes barely any difference), while the energy to swap them orthogonally to the membrane is much larger (because they would point in the wrong direction).
ajkjk · 30d ago
Oh that's neat
jjtheblunt · 31d ago
> That is one of the most incredible things I have ever read.
They shared the Nobel prize for CRISPR. Yet you chose to lead with the American one. :/
jjtheblunt · 30d ago
That's because the link I shared immediately cites Doudna and Charpentier as a team.
After edits were disabled, I thought perhaps there's a page for Charpentier too, which there was, but later than i could edit.
They're both amazing scientists.
jcims · 31d ago
She's got a couple of great appearances on RadioLab.
DrScientist · 31d ago
Bear in mind that they intentionally choose something that was soluble - ie the easiest thing possible. So it's doesn't mean everything is now solvable.
For example it's no coincidence this is a liver disease as basically almost everything you inject in the bloodstream ends up concentrating in the liver by default - if you needed to target another organ with your LNP it would be much harder. Most of the time people are trying to stop stuff accumulating in the liver!
The liver has other special properties that are helpful as well.
Having said all that - it is still a massive achievement.
> That is one of the most incredible things I have ever read.
Biology is incredible - and you can do incredible things if you leverage it.
abcd_f · 30d ago
> that was soluble
solvable
DrScientist · 30d ago
soluble has two meanings.
- able to dissolve in solvent
- able to be solved.
abcd_f · 29d ago
Is the second meaning archaic?
DrScientist · 28d ago
How old does it need to be to be archaic?
Here is a use in the title of a quite famous popular science book from the 1960's.
I had heard about CRISPR a while back but most reporting on it kind of hand waved over the mechanisms of how it actually accomplishes its work. What these researchers have figured out to make this work absolutely blows my mind.
j16sdiz · 31d ago
AFAICT, CRISPR still make many bad edits.
We relies on the fact that most of those bad edit won't survive.
rubidium · 31d ago
It can make “bad edits” eg off target effects. But in this case there were, as far as is known, none. It’s aided that this was a single nucleotide defect.
They specifically tested for off target edits in the mouse study and found no harmful edits (and very rare off target ones). That plus the specific targeting of the liver cells (no germ line effect expected), makes this a low risk approach and certainly better than doing nothing.
esalman · 31d ago
Thanks to DOGE you might read less and less about this kind of things.
shafyy · 31d ago
Unfortunately, this is true. From the article:
> The implications of the treatment go far beyond treating KJ, said Dr. Peter Marks, who was the Food and Drug Administration official overseeing gene-therapy regulation until he recently resigned over disagreements with Robert F. Kennedy Jr., the secretary of health and human services.
verisimi · 31d ago
Once the gene has been edited, things will work. But at some point that cell will die. Why would the replacement cell also have the edit? The DNA in the rest of the body's cells will still not be correct.
riffraff · 31d ago
When cells duplicate they have the same (altered) DNA so the mutated cells survive.
You'll end up with mosaicism (cells with different DNA) but presumably you have enough of the new cells to fix the problem the original ones had.
You don't need to fix all the body, you just need to fix some of the, say, liver, and you're good.
ac29 · 31d ago
> To accomplish that feat, the treatment is wrapped in fatty lipid molecules to protect it from degradation in the blood on its way to the liver, where the edit will be made. Inside the lipids are instructions that command the cells to produce an enzyme that edits the gene.
This isnt entirely unlike the method mRNA vaccines use. Through some clever biochemistry, mRNA vaccines get bits of code into cells where the cell's built in code compilers manufacture proteins that induce immunity.
We have developed software patches for our biology.
poyu · 31d ago
Made it sound like it's a computer, is it Turing complete?
koeng · 31d ago
It's fundamentally different than a computer and arguably more complete.
The talk of "crawling along the genome" is kinda fundamentally wrong though and is a bit irking - CRISPR kinda just bumps around until it hits a PAM site, in which case it starts checking against sgRNA. Much more random than they make it seem
About CRISP, it's like the ultimate Perl+Regex for the body.
dagurp · 31d ago
sounds more like sed
anthk · 29d ago
Perl and awk can do everything sed(1) does, but it an easier way.
dagurp · 27d ago
I know
drjasonharrison · 30d ago
"Bumps around until it hits" sounds like a set of magnets arranged to only mate up in a specific direction. Except we have four nucleotides rather than only two magnetic poles.
joshmarlow · 31d ago
If this thread interests you, you should check out "Blood Music" by Greg Bear. It's pretty old but the premise is that a researcher 'closes the loop' in a bunch of cells by making them able to edit their own DNA - thus making them Turing Complete.
Hilarity subsequently ensues.
dekhn · 31d ago
Cells are already able to edit their own DNA. Examples include the yeast mating switch, in which the "active" gene is replaced by one of two templates, determining the role the yeast plays in mating (https://en.wikipedia.org/wiki/Mating_of_yeast#Mechanics_of_t...)
Further, your immune system does some clever combinatorial swapping to achieve diversity (https://en.wikipedia.org/wiki/V(D)J_recombination). The generated diversity is then screened by the immune system to find highly effective antibodies that bind to specific foreign invaders.
Doing something actually interesting from an engineering perspective makes for fun science fiction, but as always, the specific details in that story would be a very unlikely outcome.
xarope · 31d ago
As I get older, I'd be happy with some minor incremental progress on addressing myopia and hyperopia.
lordnacho · 31d ago
Wouldn't it be surprising if it weren't? There's a bunch of things that are Turing complete, but they are not literally a molecular tape with machinery to read and write it.
buzzy_hacker · 31d ago
Made me think of
It was only in college, when I read Douglas Hofstadter’s Gödel, Escher, Bach, that I came to understand cells as recursively self-modifying programs. The language alone was evocative. It suggested that the embryo—DNA making RNA, RNA making protein, protein regulating the transcription of DNA into RNA—was like a small Lisp program, with macros begetting macros begetting macros, the source code containing within it all of the instructions required for life on Earth. Could anything more interesting be imagined?
Someone should have said this to me:
> Imagine a flashy spaceship lands in your backyard. The door opens and you are invited to investigate everything to see what you can learn. The technology is clearly millions of years beyond what we can make.
>
> This is biology.
–Bert Hubert, “Our Amazing Immune System”
I misread this as "fleshy" for a moment, and the quote almost works better that way.
floam · 30d ago
Me too. It did. Huh.
dekhn · 31d ago
This system isn't really turing complete, but existing biology provides everything required to make a computer which is Turing complete (assuming non-infinite tape size).
True programmatic biology is still very underdeveloped. I have seen logic gates, memory, and state machines all implemented, but I don't think anybody has built somethign with a straightforward instruction set, program counter, addressable RAM, and registers that was useful enough to justify advanced research.
Robotbeat · 31d ago
Yeah, in some ways, the genetic code and molecular biology around transcription, etc, more closely resembles the abstract Turing Machine than an actual computer does. Absolutely fascinating that the messy world of biology ends up being pretty analogous to the clean world of binary logic. Gene sizes are expressed in kilobases, where a base carries 2 bits of information.
caycep · 31d ago
I think I recall reading at least some papers or at least exercises trying to draw analogies between Turing machines and ribosome/proteonsome and other type of cellular proteins, but I can't remember back to that class some 20 years ago...
davedx · 31d ago
Sounds kind of like the infinite tape machine....
mr_toad · 30d ago
About 6 billion letters in human DNA.
fwip · 31d ago
Not really. Delivering gene edits via CRISPR in this way is more like editing a text file with a single application of a regex - `s/ACTGACTGACTG/ACTGACTGAAAAAAAACTGACTG/g`.
xarope · 31d ago
TIL my years of perl regex'ing was preparing me for a future of DNA gene warfare
(core war, anybody?)
duskwuff · 30d ago
I don't know if it still is, but, for a while, Perl was actually fairly popular in bioinformatics: https://bioperl.org/
anthk · 31d ago
So, Perl or sed. If it's Perl, the guy from XKCD was right. And, maybe, Larry Wall.
vmurthy · 31d ago
Cue the book "The Code Breaker" [0]. I read it a long time ago and such an incredible book and journey by Jennifer Doudna and Emmanuel Charpentier. Do check it out
How does it know how to gps around? From what I know everything down there is a chemical reaction with some minimal physical motion, but how do you program it to know where to change and what and how.
bglazer · 31d ago
It doesn’t know anything about where it “needs” to go. One of the weirder and more unintuitive things about molecular biology is just how fast everything moves inside a cell. The CRISPR molecule diffuses from one side of the nucleus to the other in a couple seconds and probably bumps into the entirety of the genome in a matter of minutes or hours. It’s very, very crowded inside cells, proteins and DNA and metabolites are constantly bumping into each other and are tumbling around at frankly incomprehensible rates. So, nothing needs to “know” where it needs to go, it simply gets pushed and jostled around until arrives there and then the attraction between the CRISPR’s RNA and the DNA takes over
drjasonharrison · 30d ago
This sounds so much like "simulated annealing" with reactive components and almost no lack of energy in the system. Various energies/reactions occur, which unlock or lock out other possible reactions.
Essentially you can design an rna molecular that contains a 20 nucleotide long sequence that can target your region of interest, with the caveat that there is a standard recognition sequence proximal to your sequence of interest (PAM sequence)
TheJoeMan · 31d ago
It’s more like a “ctrl+F” for DNA. Hopefully there’s only 1 match (the target site).
0x1ceb00da · 31d ago
So you create a molecule that binds to a certain location in the dna, and then deploy a billion of them?
Tuna-Fish · 31d ago
You need billions to cover multiple cells, you don't need many for a cell.
The counterintuitive part is how fast thermal motion is relative to the size of dna.
In body temperature water, the thermal velocity of water molecules jostling around everything is ~600m/s. The nucleus of a human cell is ~6µm in diameter. That is, your average water molecule bounces around at a speed that makes it move from one end of the nucleus to another roughly 100 million times per second.
Larger molecules move more slowly, but they still zip around fast enough that nothing needs to "seek" to a specific position in a cell to get there, everything will touch everything just from thermal random walk in a very short time. So how biology works is that inside the cell there might be just one messenger, which will have to hit a specific piece of dna just right in order to do anything, but that's still nearly instantaneous from our perspective.
rubidium · 31d ago
More or less, yes.
An interesting part of the study was determining what a clinical dose _should_ be. You need enough to edit enough liver cells. But don’t really want to completely overdo it to limit potentially negative side effects. Seems like they got it right enough here, with the first dose having some effect and the subsequent dose having more.
dtpro20 · 31d ago
Well its more like search and replace, where you cross your fingers that it only replaces the words you are trying replace without impacting the rest of the text in the document.
Den_VR · 30d ago
You should have seen the homebrew guy’s talk on DIY CRISPR where he injected himself on stage. And that was years ago. Incredible times for incredible work.
harhargange · 30d ago
I work on lipids and i myself didn't know they could be so much practically important.
_heimdall · 31d ago
I know someone well who works in this space, personalized gene therapy as cancer treatment.
> until it finds the exact DNA letter that needs to be changed.
This pine is disingenuous (at best). There is no way of guaranteeing where the DNA is inserted. It is designed to only slot into a very specific portion of the DNA but they don't have a way to control that precisely, the accuracy is high but "exact DNA letter" is skipping over a few pretty important details.
To be clear I'm not saying it is ineffective or unsafe, only that the claim made is marketing speak and not actually true.
Thebroser · 31d ago
The approach they used which is base editing doesn’t actually insert or remove DNA, it actually uses an enzyme to convert one base to another, which is much safer as this doesn’t require a double strand break in DNA: https://blog.addgene.org/single-base-editing-with-crispr
_heimdall · 31d ago
That is interesting, I didn't catch the difference my first time through the article.
I do still question their claim of 100% precise results though. At least based on that high level description I can definitely see it being safer, but I question any scientific claim that is an absolute.
Specific to the editing vs insertion mechanism, I question how it doesn't run into similar constraints where the mechanics of targeting exact portions of the DNA can occasionally miss or impact the wrong segment of DNA entirely.
I haven't dug as deeply down the base pair conversion though, so I could absolutely be wrong!
yieldcrv · 31d ago
Running this article through GPT and asking it more questions is one of the most incredible allocations of productivity I have ever seen
znpy · 31d ago
Yep, this is truly incredible!
fsndz · 31d ago
Never bet against science !
pishpash · 31d ago
Also presents a terrifying prospect of malicious use.
tuna-piano · 31d ago
If someone in the year 2050 was to pick out the most important news article from 2025, I won't be surprised if they choose this one.
For those who don't understand this stuff - we are now capable of editing some of a body's DNA in ways that predictably change their attributes. The baby's liver now has different (and better) DNA than the rest of its body.
We still are struggling in most cases with how to deliver the DNA update instructions into the body. But given the pace of change in this space, I expect massive improvements with this update process over time.
Combined with AI to better understand the genome, this is going to be a crazy century.
The “How to make superbabies” article demonstrates a couple of fundamental misunderstandings about genetics that make me think the authors don’t know what they’re talking about at a basic level. Zero mention of linkage disequilibrium. Zero mention of epistasis. Unquestioned assumptions of linear genotype-phenotype relationships for IQ. Seriously, the projections in their graphs into “danger zone” made me laugh out loud. This is elementary stuff that theyre missing but the entire essay is so shot through with hubris that I don’t think they’re capable of recognizing that.
cayley_graph · 31d ago
The EA community is generally incapable of self-awareness. The academic-but-totally-misinformed tone is comparable to reading LLM output. I've stopped trying to correct them, it's too much work on my part and not enough on theirs.
static_void · 30d ago
I once went into a LessWrong IRC server.
I posted a question where I referred to something by the wrong name.
Someone said I was confused / wrong, so I corrected myself and restated my question.
For some 10 minutes they just kept dogpiling on the use of the wrong term.
Never a bunch a stupider people have I met than LessWrong people.
Workaccount2 · 30d ago
Reminds me why I learned long ago to never post your code online when looking for help.
50 replies arguing about how you can simplify your for() loop syntax and not one reply with an actual answer.
Kuinox · 31d ago
What does EA means here ?
cayley_graph · 31d ago
"Effective Altruism", something I find myself aligned with but not to the extremes taken by others.
morsecodist · 31d ago
Effective Altruism is such an interesting title. Almost no one views their Altruism as ineffective. The differentiator is what makes their flavor of Altruism effective, but that's not in the title. It would be like calling the movement "real Altruism" or "good Altruism".
A good name might be rational Altruism because in practice these people are from the rationalist movement and doing Altruism, or what they feel is Altruism. But the "rationalist" title suffers from similar problems.
kmmlng · 31d ago
I suppose in the beginning, it was about finding ways to measure how effective different altruistic approaches actually are and focusing your efforts on the most effective ones. Effective then essentially means how much impact you are achieving per dollar spent. One of the more convincing ways of doing this is looking at different charitable foundations and determining how much of each dollar you donate to them actually ends up being used to fix some problem and how much ends up being absorbed by the charitable foundation itself (salaries etc.) with nothing to show for it.
They might have lost the plot somewhere along the line, but the effective altruism movement had some good ideas.
agos · 30d ago
“Measurable altruism” would have been a better name
sfink · 30d ago
> One of the more convincing ways of doing this is looking at different charitable foundations and determining how much of each dollar you donate to them actually ends up being used to fix some problem and how much ends up being absorbed by the charitable foundation itself (salaries etc.) with nothing to show for it.
Color me unconvinced. This will work for some situations. At this point, it's well known enough that it's a target that has ceased to be a good measure (Goodhart's Law).
The usual way to look at this is to look at the percentage of donations spent on administrative costs. This makes two large assumptions: (1) administrative costs have zero benefit, and (2) non-administrative costs have 100% benefit. Both are wildly wrong.
A simple counterexample: you're going to solve hunger. So you take donations, skim 0.0000001% off the top for your time because "I'm maximizing benefit, baby!", and use the rest to purchase bananas. You dump those bananas in a pile in the middle of a homeless encampment.
There are so many problems with this, but I'll stick with the simplest: in 2 weeks, you have a pile of rotten bananas and everyone is starving again. It would have been better to store some of the bananas and give them out over time, which requires space and maybe even cooling to hold inventory, which cost money, and that's money that is not directly fixing the problem.
There are so many examples of feel-good world saving that end up destroying communities and cultures, fostering dependence, promoting corruption, propping up the institutions that causing the problem, etc.
Another analogy: you make a billion dollars and put it in a trust for your grandchild to inherit the full sum when they turn 16. Your efficiency measure is at 100%! What could possibly go wrong? Could someone improve the outcome by, you know, administering the trust for you?
Smart administration can (but does not have to) increase effectiveness. Using this magical "how much of each dollar... ends up being used to fix some problem" metric is going to encourage ineffective charities and deceptive accounting.
kmmlng · 28d ago
That's fair enough, there are problems with this way of thinking. I suppose you could say the take-away should be "Don't donate to charities where close to your whole donation will be absorbed as administrative costs". There definitely are black sheep that act this way and they probably served as the original motivation for EA. It's a logical next step to come up with a way to systematically identify these black sheep. That is probably the point where this approach should have stopped.
morsecodist · 30d ago
This is a super fair summary and has shifted my thinking on this a bit thanks.
concordDance · 31d ago
The vast majority of non-EA charity givers to not expend effort on trying to find the most dollar efficient charities (or indeed pushing for quantification at all), which makes their altruism ineffectual in a world with strong competition between charities (where the winners are inevitably those who spend the most on acquiring donations).
tim333 · 30d ago
>Almost no one views their Altruism as ineffective
As someone who has occasionally given money to charities for homelessness and the like I don't really expect it to fix much. More the thought that counts.
zarathustreal · 30d ago
I like to call this “lazy altruism”
mushi01 · 31d ago
Do you really think all altruism is effective? Caring about the immediate well-being of others is not as effective as thinking in the long term. The altruism you are describing is misguided altruism, which ultimately hurts more than it helps, while effective altruism goes beyond the surface-level help in ways that don't enable self-destructing behaviours or that don't perpetuate the problem.
morsecodist · 30d ago
No I think almost all people doing altruism at least think what they are doing is effective. I totally get that they EA people believe they have found the one true way but so does do others. Even if EA is correct it just makes talking about it confusing. Imagine if Darwin has called his theory "correct biology".
alexey-salmin · 31d ago
Technically lesswrong is about rationalists not effective altruists, but you're right in a sense that it's the same breed.
They think that the key to scientific thinking is to forego the moral limitations, not to study and learn. As soon as you're free from the shackles of tradition you become 100% rational and therefore 100% correct.
jaidhyani · 31d ago
Approximately no one in the community thinks this. If you can go two days in a rationalist space without hearing about "Chesterton's Fence", I'll be impressed. No one thinks they're 100% rational nor that this is a reasonable aspiration. Traditions are generally regarded as sufficiently important that a not small amount of effort has gone into trying to build new ones. Not only is the case that no one thinks that anyone including themselves is 100% correct, but the community norm is to express credence in probabilities and convert those probabilities into bets when possible. People in the rationalist community constantly, loudly, and proudly disagree with each other, to the point that this can make it difficult to coordinate on anything. And everyone is obsessed with studying and learning, and constantly trying to come up with ways to do this more effectively.
Like, I'm sure there are people who approximately match the description you're giving here. But I've spent a lot of time around flesh-and-blood rationalists and EAs, and they violently diverge from the account you give here.
winterdeaf · 31d ago
So much vitriol. I understand it's cool to hate on EA after the SBF fiasco, but this is just smearing.
The key to scientific thinking is empiricism and rationalism. Some people in EA and lesswrong extend this to moral reasoning, but utilitarianism is not a pillar of these communities.
xrhobo · 30d ago
Empiricism and rationalism both tempered by a heavy dose of skepticism.
On the other hand, maybe that is some kind of fallacy itself. I almost want to say that "scientific thinking" should be called something else. The main issue being the lack of experiment. Using the word "science" without experiment leads to all sorts of nonsense.
A word that means "scientific thinking is much as possible without experiment" would at least embedded a dose of skepticism in the process.
The Achilles heel of rationalism is the descent into modeling complete nonsense. I should give lesswrong another chance I suppose because that would sum up my experience so far, empirically.
EA to me seems like obvious self serving nonsense. Hiding something in the obvious to avoid detection.
cnity · 31d ago
That community is basically the "r/iamverysmart" types bringing their baggage into adulthood. Almost everything I've read in that sphere is basically Dunning–Kruger to the nth degree.
stogot · 31d ago
Except no one is 100% rational nor 100% correct
JeremyNT · 30d ago
Note that these people often condescendingly refer to themselves as "rationalists," as if they've unlocked some higher level of intellectual enlightenment which the rest of us are incapable of achieving.
In reality, they're simply lay people who synthesize a lot of garbage they find on the Internet into overly verbose pseudo-intellectual blog posts filled with both the factual inaccuracies of their source material and new factual inaccuracies that they invent from whole cloth.
AlexeyBelov · 30d ago
It's like Mensa: if you really want to be a part of Mensa and be known for that, are you really that smart?
tuna-piano · 30d ago
Thanks for the healthy skepticism.
I still think there's a lot to learn from those articles for most folks uninvolved in this area, even if some of their immediate optimism has additional complications.
I think what I mostly took away is a combination of technologies is likely to dramatically change how we have babies in the future.
1. We'll make sperm/egg from skin cells. This has already been done in mice[1], so it is not science fiction to do it in people.
2. When we're able to do this inexpensively, we could create virtually unlimited embryos. We can then select the embryos that have the most optimal traits. Initially, this may be simple things like not choosing embryos with certain genes that give higher risk of certain diseases.
This may involve selecting traits like intelligence and height (there are already companies that offer this embryo selection capability [2]).
3. Instead of creating a lot of embryos and selecting the best ones, we could instead create just one embryo and edit the DNA of that embryo, which has already been done in humans [3]. Alternatively, we could edit the DNA of the sperm/egg prior to creating the embryo.
The fact that none of this is science fiction is just wild. All of these steps have already been done in animals or people. Buckle up, the future is going to be wild.
Do you have some further reading where one can understand the basics of the subject?
RandallBrown · 31d ago
Is all the DNA in the liver different, or just a percentage of the cells?
kjkjadksj · 31d ago
Easiest way to do this stuff is before fertilization when you have one egg and one sperm to work with. Delivering change through a multicellular organism is very challenging. All this stuff like transgenic mice are set up in mutant crosses before this stage, before mating really.
Eventually this will be the outcome of our species to edit the gametes themselves. The issue to overcome for this again won’t be technological as that is pretty much solved but getting people over their own “ick” factor.
something098 · 31d ago
>>>Easiest way to do this stuff is before fertilization when you have one egg and one sperm to work with.
Yes. But it seems, that nature so far is still better than we at picking better quality cells in laboratory environment. Not all eggs and sperms are equal - the difference in DNA quality varies.
>>>Eventually this will be the outcome of our species to edit the gametes themselves. The issue to overcome for this again won’t be technological as that is pretty much solved but getting people over their own “ick” factor.
This is a new fear unlocked, as this will be like another cosmetic surgery procedure, which from my minimal understanding does not affect DNA that is delivered to offsprings - that could be changed but require a lot more work, but like you mentioned - it is easier to do before fertilization :). It is catch22 situation rn.
DoctorOetker · 30d ago
>The issue to overcome for this again won’t be technological as that is pretty much solved but getting people over their own “ick” factor.
Probably requires getting investors over their profit incentive first, why treat a heritable disease for the offspring if you can charge them on a per person basis?
nextaccountic · 30d ago
> For those who don't understand this stuff - we are now capable of editing some of a body's DNA in ways that predictably change their attributes. The baby's liver now has different (and better) DNA than the rest of its body.
How to avoid having only parts of the liver with the new DNA, and some other parts with the old DNA? Like a chimeric liver - isn't this something bad?
andreygrehov · 31d ago
Are there any age restrictions?
fendy3002 · 31d ago
the usual next questions will be:
- how further can we push this to make the best, most optimized human?
- what are moral implication of this?
- what are the side effects / downsides?
kjkjadksj · 31d ago
Low hanging fruit is very low hanging in this case. There are many point mutations for example that confer risk to disease and cancer. Lynch syndrome which confers significant risk for colorectal cancer for example is something that could he cured with transgenic humans today even with todays technology. Just a matter of screening gametes for the mutation (usually one base in the case of Lynch in heterozygous state with wild type healthy allele and that wild type healthy allele gets a second hit mutation as the cancer develops and things just go off the rails from there) and editing that base back to wildtype. No downside only upside with that.
What gets harder are polygenic traits that even today we don’t have great data on what are the causal alleles. But that is also not a technological limitation either but a statistical one from insufficient sampling of these polygenic phenotypes.
flakeoil · 31d ago
I also wonder what happens if this kid one day has kids. In this case it was a very rare genetic disease, but if the same was applied to a less rare genetic disease (where it is also more beneficial to have a treatment as more people have use of it) wouldn't the end result be that more and more kids will be born with these diseases?
eimrine · 30d ago
I hope we can not just heal a disease for one phenotype, but cure it for the whole breed.
xvilka · 30d ago
There's no "most optimized human". We are already that, perfected in millions of years. What could really happen is the split between multiple sub-species. For example, it makes perfect sense to do the optimization for orbital station dwellers or Mars colonists or underwater dwellers.
mr_toad · 30d ago
We’re not perfect, we’re just good enough to have survived.
There are lots of hereditary illnesses and conditions that could probably be tweaked with DNA editing, if we can identify the responsible genes. If someone can cure male pattern baldness they’ll be rich.
Panzer04 · 31d ago
Can it be applied to adults? Useless for this particular disorder, but what about others?
rob74 · 31d ago
That's all very cool, but there are also articles like this one: https://www.theguardian.com/us-news/2025/feb/20/trump-nih-cu... - I'm not able to read the Times article because it's paywalled, but as other commenters have mentioned, this research was funded by the NIH, which the Trump administration is currently in the process of defunding. So, if further progress along this road will be made, it'll probably be much slower and less likely to be in the US.
cnity · 31d ago
Or, it means that funding will be secured in the private sector. Basically by investors that focus on revenue streams (read: extremely expensive private healthcare).
rob74 · 30d ago
Yeah, maybe for stuff like this which (now) has direct applications, yes. But for basic research (and it took decades of basic research on genetics, gene editing etc. etc. to get to this point)? No way...
As a father, the idea of being told my 1 week old baby is going to die would be my worst nightmare. The fact these doctors and scientists saved this childs life is a monument to modern medical science. This is absolutely insane. Hopefully the child doesnt need a liver transplant, but this is a great leap forward.
bilekas · 31d ago
> But KJ’s treatment — which built on decades of federally funded research — offers a new path for companies to develop personalized treatments without going through years of expensive development and testing.
Really incredible story and I'd love to know the process for receiving this, for example FDA approval etc. It's nice to see such in-your-face results from Federal funding programs. Without being political, it's sometimes hard for regular people to appreciate just how much good actually comes out of Federal Funding. There was another thread where someone even said something along the lines of : "Well during war things get done faster" . This simply isn't true. It might be done louder but Federal Funding never stopped pushing things forward.
jjeaff · 31d ago
I'm not an expert, but I have learned that FDA approval is not actually necessary for treatments and drugs. Your doctor has a lot of leeway when it comes to treatment but she of course experiences more risk of accusations of malpractice when prescribing off label drugs or unapproved treatments. insurance will also rarely cover treatment that is not FDA approved. the requirement for FDA approval generally has more to do with your legal ability to market the drug, treatment, or product.
bilekas · 31d ago
That's actually super interesting and kinda great to hear, I guess my follow up question is obvious but would insurance companies cover that kind of procedure in the US? I get the impression it wouldn't be.. but if out of pocket.. I know I'd absolutely do anything for my kid.
baxtr · 31d ago
Now imagine DOGE team of experts cutting this a couple of years ago
0_____0 · 31d ago
Here's the thing - likely few would have noticed. We are structurally blind to the places in which public investment would have made our lives better, especially when they are things like scientific research that the vast majority never think about until it produces results.
bilekas · 31d ago
I didn't want to bring up specifics but I'd be lying if it wasn't on my mind.
munificent · 31d ago
I mean, the article is explicitly written to put it on your mind:
"The implications of the treatment go far beyond treating KJ, said Dr. Peter Marks, who was the Food and Drug Administration official overseeing gene-therapy regulation until he recently resigned over disagreements with Robert F. Kennedy Jr., the secretary of health and human services."
"But KJ’s treatment — which built on decades of federally funded research"
"The result “is a triumph for the American peoples’ investment in biomedical research,” Dr. Urnov said."
"The researchers emphasized the role government funding played in the development."
"The work, they said, began decades ago with federal funding for basic research on bacterial immune systems. That led eventually, with more federal support, to the discovery of CRISPR. Federal investment in sequencing the human genome made it possible to identify KJ’s mutation. U.S. funding supported Dr. Liu’s lab and its editing discovery. A federal program to study gene editing supported Dr. Musunuru’s research. Going along in parallel was federally funded work that led to an understanding of KJ’s disease."
"“I don’t think this could have happened in any country other than the U.S.,” Dr. Urnov said."
This is an article about federal funding of medical research with a cute baby as the human interest bit.
No comments yet
shadowgovt · 31d ago
It would probably be good if more of us brought up specifics more often.
bilekas · 31d ago
It would be nice, but you know how politics can usually turn into a bit of a toxic environment online. That said, I personally don't see the DOGE thing as anything other than a way to reduce the power of regulatory enforcement. I'm sure someone who would want that would never be conflicted with interests there...
tempaway43563 · 31d ago
they were able to develop the treatment and fast track it through the FDA in six months, details in this write-up
NYT isn’t super specific here, but they made it sound like the disease treated is liver related. My understanding is that the liver is a good place to start with CRISPR-type gene treatments, in that the liver normally deals with anomalous shit in your bloodstream, say, like CRISPR type edits. So anywhere outside the liver is going to be significantly harder to get really broad uptake of gene edits.
It’s crazy encouraging that this worked out for this kid, and I’m somewhat shocked this treatment was approved in the US - I don’t think of us as very aggressive in areas like this. But to me, really hopeful and interesting.
cdcox · 31d ago
You are right, current CRISPR systems tends to accumulate in the liver. Most CRISPR companies have shifted their focus to the liver over time because it's easiest to deliver there. Most viruses people use to target other organs are not large enough to carry CRISPR and lipid nanoparticles with CRISPR seem to like ending up in the liver and are hard to deliver at dose to hit other organ systems. It has been one of the big struggles of CRISPR companies. That being said, this is a huge deal and very encouraging.
As to the FDA stance, it tends to be more willing to go ahead with compassionate uses like this when it's clearly life or death.[1]
People born with this lack the enzyme CPS1, which screws up the urea cycle and causes a build up of ammonia. Ammonia build up is bad for your nervous system.
oceansky · 31d ago
It is caused by a missing enzyme in the liver, yes.
scotty79 · 31d ago
I don't think it's gonna be that hard. All cells that blood reaches were happily taking mRNA vaccine.
derektank · 31d ago
I hate to break it to you, but it will be substantially more difficult to target other organ systems. The liver is uniquely easy to target with our current vectors.
Right off the bat, the liver receives roughly a quarter of all cardiac output, either directly or second hand from the digestive organs. Additionally, the liver has a fenestrated endothelium which, while not completely unique in the body, uniquely allows molecules like lipid nanoparticles (LNPs) to access liver cells. Finally, the liver is the site of most lipoprotein processing, and LNPs can be designed to take advantage of the existing pathways to get the gene editing mRNA into the hepatocytes. All this is to say that if you have a genetic condition that primarily effects the liver, there's a lot more hope for treatment in the near term than for others.
Good lecture on the difficulties of finding appropriate platforms for delivering gene therapies to cells for anyone interested [1]
No they were not. A vaccine triggers an immune response, not a functional change.
mRNA vaccines are highly localized: you get a sore arm because most of it only gets taken up by muscle cells around the injection site, which spend some time producing the antigen and triggering a primary immune response (the inflammation aka the sore arm).
xrhobo · 30d ago
What I find interesting about the covid mRNA vaccine is I remember being sick in March 2020 and I can't remember being sick since.
I can remember getting a sniffle at night and waking up fine the next morning a few times.
I think I had two doses of covid mRNA vaccine.
I have actually forgot what it is like to be sick. It almost feels like the covid vaccine gave me some kind of super immunity. I never get the flu shot either. I have not had the flu in 5 years for sure.
BrawnyBadger53 · 30d ago
I think this is more likely a result of increased standards of cleanliness that have remained
scotty79 · 31d ago
Still it needs to enter the cells all the same.
As for being localized it's true however after vaccine dose S proteins have been detected also in remote locations in the body because you can't make something 100% localized.
If you had an infusion that doesn't trigger immune system you could just increase the dose significantly, put it in the blood and most likely it would have reached all cells that blood reaches.
im3w1l · 31d ago
Last I heard those gene editing things lead to so called of-target edits, so they were basically corrupting random dna. Now in this case the baby would have died without this treatment so clearly benefits outweight the risks. But even then they probably want to have the dose be as low as possible.
But I'm speculating a bit here.
danielodievich · 31d ago
When my second son was born and was just so very tiny some genetic test came out questionable. We were very strongly encouraged to go to Childrens hospital ASAP to get more tests. He handled it well, being just a few weeks old. The tests came with "he's a carrier of something obscure but nothing to worry about", so it's all forgotten.
Three interesting thing come out of it from me. First, I was on Microsoft insurance which was quite gold plated at a time, a blessing only obvious in rear-view mirror, because Childrens was quite excited to continue any number of tests. Second, the technology of all this is absolutely amazing and I am so happy that it was available to me, and it has likely gotten better. Three, I want that tech to continue to expand and current destruction up there is going to hand this torch to someone else, which makes me sad.
jjcm · 31d ago
> I was on Microsoft insurance which was quite gold plated at a time
One of the biggest perks of working for Microsoft for a long time was their health coverage. I can't tell you the number of times I'd be doing initial paperwork for a doctor's appointment and the receptionist would be like, "Oh you have THAT insurance, we're going to do all of the tests." I've heard they since cut back on it a little, but it truly was gold plated.
burnt-resistor · 31d ago
Circa 2005, Stanford FTEs had nine (9) health insurance plan choices. ;P
dmurray · 31d ago
Is that better or worse than having one really good one?
burnt-resistor · 30d ago
;) Paradox of choice potentially, but allowed choosing something other than Kaiser Permanente (HMO with own facilities and doctors) such as a PPO option.
What America really needs is an NHS not tied to employment or exploited by fraudsters delivering worse care for profit. Human rights shouldn't be perks of employment.
bigtones · 31d ago
My niece in Australia has a rare genetic disorder and when my wife and I had our first baby in California a few years ago we were concerned about that. We also had fantastic insurance and the hospital team there did a test where they took a blood sample from my wife and seperated the childs DNA from the mothers in the blood sample and tested it for several genetic disorders. That test is not available in Australia even today.
skissane · 31d ago
> That test is not available in Australia even today.
Pretty much every lab test is available in Australia if you are willing to pay for it; if they don’t have a local lab capable of running the test, they’ll send the sample overseas
The real question is whether it is covered by insurance or not, and a lot of the time the answer is “no” - I recently forked out over US$500 for genetic tests on one of our kids (which the paediatrician recommended), although the results weren’t particularly helpful (“rare variant of uncertain clinical significance”)
ykl · 31d ago
Incredibly that test (cell-free fetal DNA - cfDNA) is now standard in California, to the point where most expecting parents in California now learn the baby’s gender super early. We learned our baby’s gender only 10 weeks into pregnancy because of the cfDNA test.
palisade · 31d ago
Does this mean when they grow up, their own offspring will also have this defect and require a correction? And, if so, does this mean it is now introducing this defective gene into our gene pool?
I know this is an issue with caesarean section. It is becoming more prevalent because those who require it are surviving, making it more likely to happen in their offspring.
foreigner · 31d ago
We get half of our genes from each of our parents. So unless this person has the extremely unlikely misfortune of partnering with someone else with the same rare mutation, their offspring would only have a 50/50 chance of inheriting their copy of this gene. There are also medical procedures (PGD) to bring that chance to virtually 0%.
something098 · 31d ago
We don't get 50/50 of distinct genes from our parents - it is more like 30/70 and can be even 10/90. The whole DNA ratio in this equation is irrelevant, as we all have 99% of the same DNA. Also, in real world, one parent will consistently give more of their distinct genes than other parent and most likely that consistent gene part will have that single mutation that they would hope to avoid, but contain best genes that the parent can offer. Children from multiple partners could be a solution as it is a different math...
>>>There are also medical procedures (PGD) to bring that chance to virtually 0%.
For that one gene only.
DNA is a math of sum of genes and from what I have read humans are not better than nature(which is not perfect, but very basic) at selecting best specimens of eggs and sperm, but yes - whatever they have picked - PGD might be able to root out that one single mutation, and introduce variety of other mutations or miss good genes from other combinations. So, it all depends...
Sammi · 31d ago
Also parents who are both carriers have a 25% chance of making a sick child, a 25% chance of making a non carrier and non sick child, and a 25%+25% chance of making non sick yet carrier child. So they already have a 50% chance of making children who'll survive and yet be carriers of the disease. I guess this will increase this to 75%. But you have to evaluate this in connection with the rapid increases in genetic treatment options, which decreases the issues.
rkangel · 31d ago
> know this is an issue with caesarean section. It is becoming more prevalent because those who require it are surviving
You state this as a fact and I've heard it as a strong hypothesis, but I wasn't aware of much evidence to confirm it?
palisade · 31d ago
"The cesarean delivery rate increased from 5% in 1970 to 31.9% in 2016. This sharp increase can be attributed to various factors, including changes in maternal age, medical advancements allowing more complicated pregnancies to proceed, and evolving obstetric practices. In 2022, the United States recorded more than 3.66 million births, most of which resulted from spontaneous or induced labor. Labor dystocia remains the most common indication for primary cesarean delivery. Globally, cesarean delivery rates continue to rise, and reducing unnecessary cesarean procedures remains a priority in the United States, where 32.2% of all births in 2022 were cesarean deliveries."
"If this trend continues, by 2030 the highest rates are likely to be in Eastern Asia (63%), Latin America and the Caribbean (54%), Western Asia (50%), Northern Africa (48%) Southern Europe (47%) and Australia and New Zealand (45%), the research suggests."
Note: Coincidentally, WHO's article I've linked is lamenting that Sub-saharan Africa only had 5% cesarean due to less availability of the procedure. It is their perspective that the increase in percentages is a good thing and indicates progress, instead of being concerning. And, they find Sub-saharan Africa's low numbers concerning, instead.
Side Note: I also found lots of interesting articles which I haven't posted here, about epigenetic side effects caused by caesarean deliveries like leukemia, illnesses and other genetic issues. But, that seems out of scope for your question. You can make a quick search and find these, though.
"A female-to-female familial predisposition to caesarean section was observed. It could be caused by biologic inheritance, primarily working through maternal alleles and/or environmental factors. The results imply that both mechanisms could be important."
"Large-scale epidemiological studies indeed evidence that women born by C-section are more likely to deliver by Caesarean than women born vaginally, owing primarily to genetic rather than social factors."
> Another Note: Also, ironically WHO's article I've linked is lamenting that Sub-saharan Africa only had 5% cesarean due to less availability of the procedure. It is their perspective that the increase in percentages is a good thing and indicates progress, instead of being concerning. And, they find Sub-saharan Africa's low numbers concerning, instead.
Pretty sure their perspective is that "saving the lives of mothers and babies" indicates progress.
> While a caesarean section can be an essential and lifesaving surgery, it can put women and babies at unnecessary risk of short- and long-term health problems if performed when there is not medical need.
> Rather than recommending specific target rates, WHO underscores the importance of focusing on each woman’s unique needs in pregnancy and childbirth.
> WHO recommends some non-clinical actions that can reduce medically unnecessary use of caesarean sections, within the overall context of high quality and respectful care:
palisade · 30d ago
Yes, that's what they're indicating. And, it is saving lives. I myself was cesarean section, as was my mother. I wouldn't be here without it.
That's the potential conundrum, if it turns out to be vastly increasing the need to save those lives than in the past due to a evolutionary pressure on the gene pool. If the WHO is right and we're going to start seeing 50 - 63% increases by 2030, what's in store for the human race if this rate of expansion keeps up?
Will we reach a time when no one can be naturally born and almost our entire race has to be conceived in external gestation devices or cease to exist? And, when we reach that point will we look with concern towards Africa and wonder at how sad it is they're still conceived naturally.
Edit: I don't have the answers. I'm not sure what we should do to course correct or if we need to. But, it is definitely something that should be looked into before it is too late, if it isn't already. And, that is why I brought it up in the context of this breakthrough, to ask if we've considered similar consequences. And, if we have a way to mitigate them if that turns out to be the case.
squigz · 30d ago
> Edit Edit: I can't reply to your comment below I think we've hit the leaf end of this post. But, to reply to your question are c-sections replacing natural births or are they just becoming more common? The research I've cited has indicated this is a genetic transfer among female-to-female births of a need for more cesareans.
To reply after a certain number of child comments, you have to open the comment by clicking the timestamp thing
I'm also afraid I don't understand your response. Can you elaborate?
palisade · 30d ago
Thanks, I replied to your other comment.
squigz · 30d ago
Are c-sections replacing 'natural' births, or are they simply becoming more common because we have the expertise? There is a difference
palisade · 30d ago
The research I've cited has indicated this is a genetic transfer among female-to-female births of a need for more cesareans.
"A female-to-female familial predisposition to caesarean section was observed. It could be caused by biologic inheritance, primarily working through maternal alleles and/or environmental factors. The results imply that both mechanisms could be important."
"Large-scale epidemiological studies indeed evidence that women born by C-section are more likely to deliver by Caesarean than women born vaginally, owing primarily to genetic rather than social factors."
> "Large-scale epidemiological studies indeed evidence that women born by C-section are more likely to deliver by Caesarean than women born vaginally, owing primarily to genetic rather than social factors."
Interesting. That makes sense. I wonder if the type of research being pursued in TFA might be helpful.
In any case, I also have to wonder whether it's necessarily a bad thing. I quoted 'natural' births earlier because... what is natural? The amount of medical knowledge and technology that go into births doesn't seem very "natural" to me, and this has advanced through the ages to where we are now - where we, rightfully so, look sadly on areas where lack of such technology and knowledge result in more preventable deaths of babies, even if their methods are more "natural"
Of course, to be honest, I'm not very familiar with the pros and cons of c-sections vs natural births - particularly when the question is whether to have a child. I suppose that, given the choice between a c-section and the alternatives, most women will opt for a c-section, and as you point out, that means their daughters likely will have to as well
So what might the solution even look like, apart from exploring the aforementioned gene-editing technology - or other technology - to prevent the genetic factor of c-sections? I would hope that "don't offer c-sections" is not a serious option. "Stop having kids" is one I'd personally suggest, but that's obviously not a sane global solution either.
It's an interesting problem I'd be curious to hear more about - as I said, I'm not very familiar with this.
No comments yet
rkangel · 31d ago
Interesting - thank you!
Tade0 · 30d ago
Research is inconclusive regarding what exactly causes this increase.
We know that infants are generally larger than 50 years ago and one of the factors which trigger birth is the inability of the mother's metabolism to support further growth of the fetus.
That, combined with the fact that all over the world availability of nutrition is much better than half a century ago points to this being the culprit.
mondaygreens · 31d ago
How can they pass it on when they don't have the defect any more?
nahsra · 31d ago
Gene editing is still pretty crude in terms of delivery.
Just because you can hit some germ-line cells in the liver, for example, doesn’t imply you’ll have good penetration into the reproductive organs.
We can’t zap people and change all their DNA at once, unless we can intervene at the point it’s just a few cells.
raldi · 31d ago
The DNA was only edited in the liver. But by the time this baby grows up and starts a family, we'll probably be able to fix that, too.
aucisson_masque · 31d ago
That's a bold claim. The baby is 9 month old, there are many things that can still go wrong with this experimental treatment.
Hopefully not, but even then no one can say what progress will make science in the next 25 years.
Back in the 50's people thought we would be driving in flying car in 2000.
You can't compare that to gene-editing treatments, that's two completely different level.
Self driving car were always almost feasible, 20 years ago top gear made cars you could drive with controller like kids do with toy cars. We already had camera and computer, it was just a matter of raw CPU performance and software development..
bdangubic · 30d ago
we have all the CPU performance we need and all software development we need and self-driving cars are driving around in roughly 0.00785% of world’s cities :)
pishpash · 31d ago
If by "they" you mean their gametes, those were not edited. Only a component of their corporal shell was modified.
poilcn · 31d ago
It only affects some cells, not the whole body.
make3 · 31d ago
they could CRISPR his relevant reproductive cells, this general topic is an important subject of discussion
something098 · 31d ago
Ah, yes - few million of them. Simple task for sure, if the liver is functioning as testes.
This is something I have never seen for decades - a troll that posts links to his own quotes...
We met again.
Brystephor · 31d ago
This is incredible work. Its jaw dropping to learn that something like this is possible at all. Sometimes I wish I could work for a company whose products make a meaningful positive contribution to the work.
Do companies like this have a need for SWEs? Are there opportunities for a backend SWE without any background in hardware or biology?
armedgorilla · 30d ago
I run a small software team at a small biotech working on diseases with small patient populations, and the answer is yes x 1000. The issue is that in drug companies, software isn't the product, so SWEs will never make as much money nor be as much of a priority as in tech-proper.
There are two categories of software we need help with:
1. Salesforce for science. We don't have big data in terms of volume; we have big data in terms of heterogeneity. Tons of small data sets that need context to be interpreted, including measuring uncertainty. This software, often called an eLN or LIMS, is offered by expensive vendors who each have their custom, locked-in implementations. Every organization needs customization on top of this that can be developed and change with the changing direction of the bench scientists.
2. Informatics tools. Much of the heavier computational tools (bioinformatics, molecular dynamics, stats) were developed by academic labs, who don't have the training or incentives to create sustainable software. Alternatively, they are made by vendors who write software on short-term contracts, so they don't have expertise in house. Our mass spec vendor told us to put their analysis servers on our Citrix so employees could access it. Citrix! If you can convince those vendor to hire you and rewrite their software, please do.
Despite cool tools like alphafold making headlines, the software needs in drug development are more mundane. We need people who are excited to sit down with bench scientists and help them figure out how very normal tools can be applied to their work.
globular-toast · 31d ago
> Do companies like this have a need for SWEs? Are there opportunities for a backend SWE without any background in hardware or biology?
Of course they do. Biology and medical research can't get enough software people. But they're not as well funded as advertising or spying companies, for example, so you might have to take a significant pay cut.
I wouldn't pigeon hole yourself as a "backend engineer". Why do people do that? Software is software. The bit that matters is the core model and algorithms etc. Whether it's exposed as a web server, a CLI or just a library is a peripheral detail.
It's totally possible for a decent software engineer to learn just enough biology to get by. The limiting factor might be your interest, though. But if you have that then go for it. Get a book on genomics right now.
rubidium · 31d ago
Yes. Aldevron and IDT are two companies (owned by danaher) that collaborated to make this happen. They have multiple authors listed in the NEJM article.
Mark Behlke's group at IDT is the force behind a LOT of the development of CRISPR, but they are relatively unknown
thesparks · 30d ago
My daughter has a genetic condition (PKU) that is also caused by a single letter change in her DNA and also causes brain damage if she consumes too much protein. Luckily it can be controlled with a strict low-protein diet (<10 grams a day).
This is SO exciting! The fact that there is a chance of a cure has absolutely made my day!
ckemere · 30d ago
The work outlined in the actual paper is quite remarkable. Within this 6 month period they generated transgenic mice with the precise mutations (paternal and maternal) this baby had in order to test treatment for functionality and toxicity as well as a doing a toxicity study in monkeys.
To those thinking about commercialization opportunities, these two steps seem the most labor intensive and time consuming, but also the most necessary in order to actually have confidence to inject completely customized gene editing therapy in a kid.
(Also worth highlighting for folks opposed to animal research.)
burnt-resistor · 31d ago
Hmm, I thought clinical gene editing (gene therapy) was frowned upon because it's inherently risky and fraught with ethical hazards. What technically and ethically has changed since 2005 beyond CRISPR?
bglazer · 31d ago
Germline gene editing is still considered risky and unethical. That is, editing cells that form eggs and sperm, thus changing the genome of some of the descendants of the edited person. This is somatic editing. These edits will not be inherited.
Somatic editing is becoming more common (see Casgevy) but there are technical hurdles that prevent its application to many cases.
zharknado · 31d ago
> This is somatic editing. These edits will not be inherited.
Genuine question- how do we know that? Is it just that the edits are very improbable to accumulate in the gonads in sufficient quantities to persist? We can’t actually prevent some fraction of them from reaching other parts of the body, right?
burnt-resistor · 30d ago
I'd like to know that too. When a gene therapy is administered to a person after birth, what % of cells get the edit and with what approach(es)? Doesn't that also edit oocytes and spermatocytes too?
colechristensen · 31d ago
>KJ has made medical history. The baby, now 9 ½ months old, became the first patient of any age to have a custom gene-editing treatment, according to his doctors.
This is _not_ the first human to be treated with a treatment under the wide umbrella of gene therapy based on their own edited genes. There probably is a more narrow first here but the technical details get lost in journalism which is a shame.
jfarlow · 31d ago
"Custom" in that this therapy was designed AFTER a specific patient showed a need, and then given to _that_ patient. In most every other context a particular class of disease is known, a drug designed, and then patients sought that have that disease that matches the purpose of the drug.
What's intriguing is not the 'custom' part, but the speed part (which permits it to be custom). Part of what makes CRISPR so powerful is that it can easily be 'adjusted' to work on different sequences based on a quick (DNA) string change - a day or two. Prior custom protein engineering would take minimum of months at full speed to 'adjust'.
That ease of manipulating DNA strings to enable rapid turnaround is similar to the difference between old-school protein based vaccines and the mRNA based vaccines. When you're manipulating 'source code' nucleic acid sequences you can move very quickly compared to manipulating the 'compiled' protein.
caycep · 31d ago
I want to say, maybe it's better to say first human under proper IRB/regulatory compliance. Some rogue academic in China tried it a few years ago, if I recall, but with absolutely no oversight and he was pilloried. Also I don't think there is much details about what he actually did...
And an Editorial piece (more technical than the NYT): https://www.nejm.org/doi/full/10.1056/NEJMe2505721
That is one of the most incredible things I have ever read.
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://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.
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?
It's easy to find papers discussing the problem, just search Google Scholar. Example:
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp...
Integration was proven in 2024, unfortunately :(
https://www.medrxiv.org/content/10.1101/2024.03.24.24304286v...
"Of the S1 positive post-vaccination patients, we demonstrated by liquid chromatography/ mass spectrometry that these CD16+ cells from post-vaccination patients from all 4 vaccine manufacturers contained S1, S1 mutant and S2 peptide sequences"
They can tell the difference between vaccine spike and virus spike as the vaccine spike was modified for stability. The exact pathway is speculated to have been DNA contamination due to manufacturing process defects. Sequencing of vaccine vials has shown far higher levels of DNA contamination than is considered safe, and the lipids would bring DNA into the cells just as well as they do mRNA making the safe levels much lower still.
https://osf.io/b9t7m_v1/download/
https://www.medrxiv.org/content/10.1101/2024.03.24.24304286v...
But yes further study has to be made.
If anyone else does know, please chime in!
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.
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.
Given the merry movement to call the COVID vaccines gene editing, it rankles.
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!
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.
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?
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.
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...
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.
Additionally, that “if you can find them” is doing some pretty heavy lifting. The range of explosives and kinetics is hilariously low, and the actual percentage of your military with the level of mobility he seems to be referring to is infinitesimal.
This argument more correctly explains why chemical weapons aren’t a great defense against precision strike groups. It also doesn’t get into detail with concepts like dropping a bomb right in the middle of a firefight knowing it literally cannot harm your own troops, short of the physical metal accidentally falling on one of your own troops.
Yes, it isn't effective outcome in terms of meeting their objective
> It also doesn’t get into detail with concepts like dropping a bomb right in the middle of a firefight knowing it literally cannot harm your own troops
That's a video games logic, it doesn't work like that in practice. Even civil grade riot control tear gas grenade is pretty traumatic because it still explodes to disperse the gas (source : implied first hand knowledge). That and warfare is messy, which means half the time half the protective gear will be destroyed from the usual exploding and shooting happening, gas gets carried away by the wind in a random direction, etc, etc.
No, it’s science. There are about a million ways to protect your own troops if that’s actually what you want to do.
It feels like you’re arguing against the idea of chemical weapons from the 1940s, rather than nearly a century later.
You don’t need protective gear. You can create sprays, lotions, inhalants, and other countermeasures that don’t stop working the second a piece of cloth rips. Shit, You could make a biological agent that avoids a DNA marker created with an mRNA vaccine. Likely not nearly as fast, but perfectly lethal.
Modern chemical weapons and biological weapons are absolutely incomparable to their Vietnam counterparts.
A terror attack on civilians is a lot different than modern militaries using them on each other.
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)
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.
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.
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.
Assuming requisite safety of course.
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.
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.
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.)
I am, afraid, that this kind of genome modification will further increase divide in a society and turn social lifts off even more. I.e. it's not gonna be your kid to get "improve" brain genes first, and later your kid wouldn't get a chance to get it ever again for their children.
Just to be clear I'm not against of the progress, this thing is fascinating and really shows how awesome humans are. And I get why you'll get it if possible for your kid. I'm just not sure its benefits for the society mean it's gonna be anyhow affordable for regular people.
> 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.
[And no, I am not anti-vax, nor anti-gene-editing.]
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.
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.
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.
I'm not going to claim that I know the perfect place to draw the line.
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.
To me the wildest scenarios take this off the table.
One of the treatments for sickle-cell involves switching off the gene that makes the malfunctioning red blood cells, but of course that's not sufficient; you'd stop making red blood cells completely and you'd die. So it's combined with a modification that switches on a gene that all humans express pre-birth that causes your body to make "super-blood": red blood cells with significantly more binding points for oxygen. This is necessary because a fetus gets oxygen from its mother's blood, so the increased binding affinity is useful for pulling the oxygen towards the fetus at the placental interface. After birth, expression of that gene is disabled and regular RBC genes switch on.
So the therapy doesn't "fix" sickle RBCs; it disables the body's ability to make them and re-enables fetal RBCs! I have seen no literature on whether having fetal RBCs in adulthood has any benefits or drawbacks (besides changing the affinity ratio for their fetus if the patient gets pregnant, I imagine increased-affinity RBC could help for athletics... But I also imagine it requires more iron to generate them so has dietary impact).
From shadowgovt:
> I have seen no literature on whether having fetal RBCs in adulthood has any benefits or drawbacks (besides changing the affinity ratio for their fetus if the patient gets pregnant
This was exactly the question that popped into my mind when I read about switching from normal adult RBCs to fetal RBCs: does this therapy reduce the likelihood of carrying a baby to term?
No problems really..never knew I had it until I was told I had thalassemia trait as part of genetic testing. My hemoglobin panel shows fetal hemoglobin.
This is even more great reading behind the above:
https://en.wikipedia.org/wiki/Jennifer_Doudna
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https://www.sciencehistory.org/stories/magazine/the-death-of...
https://en.m.wikipedia.org/wiki/Emmanuelle_Charpentier
After edits were disabled, I thought perhaps there's a page for Charpentier too, which there was, but later than i could edit.
They're both amazing scientists.
For example it's no coincidence this is a liver disease as basically almost everything you inject in the bloodstream ends up concentrating in the liver by default - if you needed to target another organ with your LNP it would be much harder. Most of the time people are trying to stop stuff accumulating in the liver!
The liver has other special properties that are helpful as well.
Having said all that - it is still a massive achievement.
> That is one of the most incredible things I have ever read.
Biology is incredible - and you can do incredible things if you leverage it.
solvable
- able to dissolve in solvent
- able to be solved.
Here is a use in the title of a quite famous popular science book from the 1960's.
https://www.routledge.com/The-Art-of-the-Soluble/Medawar/p/b...
I had heard about CRISPR a while back but most reporting on it kind of hand waved over the mechanisms of how it actually accomplishes its work. What these researchers have figured out to make this work absolutely blows my mind.
They specifically tested for off target edits in the mouse study and found no harmful edits (and very rare off target ones). That plus the specific targeting of the liver cells (no germ line effect expected), makes this a low risk approach and certainly better than doing nothing.
> The implications of the treatment go far beyond treating KJ, said Dr. Peter Marks, who was the Food and Drug Administration official overseeing gene-therapy regulation until he recently resigned over disagreements with Robert F. Kennedy Jr., the secretary of health and human services.
You'll end up with mosaicism (cells with different DNA) but presumably you have enough of the new cells to fix the problem the original ones had.
You don't need to fix all the body, you just need to fix some of the, say, liver, and you're good.
This isnt entirely unlike the method mRNA vaccines use. Through some clever biochemistry, mRNA vaccines get bits of code into cells where the cell's built in code compilers manufacture proteins that induce immunity.
We have developed software patches for our biology.
The talk of "crawling along the genome" is kinda fundamentally wrong though and is a bit irking - CRISPR kinda just bumps around until it hits a PAM site, in which case it starts checking against sgRNA. Much more random than they make it seem
About CRISP, it's like the ultimate Perl+Regex for the body.
Hilarity subsequently ensues.
Further, your immune system does some clever combinatorial swapping to achieve diversity (https://en.wikipedia.org/wiki/V(D)J_recombination). The generated diversity is then screened by the immune system to find highly effective antibodies that bind to specific foreign invaders.
Doing something actually interesting from an engineering perspective makes for fun science fiction, but as always, the specific details in that story would be a very unlikely outcome.
I misread this as "fleshy" for a moment, and the quote almost works better that way.
True programmatic biology is still very underdeveloped. I have seen logic gates, memory, and state machines all implemented, but I don't think anybody has built somethign with a straightforward instruction set, program counter, addressable RAM, and registers that was useful enough to justify advanced research.
(core war, anybody?)
https://en.wikipedia.org/wiki/The_Code_Breaker
Essentially you can design an rna molecular that contains a 20 nucleotide long sequence that can target your region of interest, with the caveat that there is a standard recognition sequence proximal to your sequence of interest (PAM sequence)
The counterintuitive part is how fast thermal motion is relative to the size of dna.
In body temperature water, the thermal velocity of water molecules jostling around everything is ~600m/s. The nucleus of a human cell is ~6µm in diameter. That is, your average water molecule bounces around at a speed that makes it move from one end of the nucleus to another roughly 100 million times per second.
Larger molecules move more slowly, but they still zip around fast enough that nothing needs to "seek" to a specific position in a cell to get there, everything will touch everything just from thermal random walk in a very short time. So how biology works is that inside the cell there might be just one messenger, which will have to hit a specific piece of dna just right in order to do anything, but that's still nearly instantaneous from our perspective.
An interesting part of the study was determining what a clinical dose _should_ be. You need enough to edit enough liver cells. But don’t really want to completely overdo it to limit potentially negative side effects. Seems like they got it right enough here, with the first dose having some effect and the subsequent dose having more.
> until it finds the exact DNA letter that needs to be changed.
This pine is disingenuous (at best). There is no way of guaranteeing where the DNA is inserted. It is designed to only slot into a very specific portion of the DNA but they don't have a way to control that precisely, the accuracy is high but "exact DNA letter" is skipping over a few pretty important details.
To be clear I'm not saying it is ineffective or unsafe, only that the claim made is marketing speak and not actually true.
I do still question their claim of 100% precise results though. At least based on that high level description I can definitely see it being safer, but I question any scientific claim that is an absolute.
Specific to the editing vs insertion mechanism, I question how it doesn't run into similar constraints where the mechanics of targeting exact portions of the DNA can occasionally miss or impact the wrong segment of DNA entirely.
I haven't dug as deeply down the base pair conversion though, so I could absolutely be wrong!
For those who don't understand this stuff - we are now capable of editing some of a body's DNA in ways that predictably change their attributes. The baby's liver now has different (and better) DNA than the rest of its body.
We still are struggling in most cases with how to deliver the DNA update instructions into the body. But given the pace of change in this space, I expect massive improvements with this update process over time.
Combined with AI to better understand the genome, this is going to be a crazy century.
Further reading on related topics:
https://www.lesswrong.com/posts/JEhW3HDMKzekDShva/significan...
https://www.lesswrong.com/posts/DfrSZaf3JC8vJdbZL/how-to-mak...
https://www.lesswrong.com/posts/yT22RcWrxZcXyGjsA/how-to-hav...
I posted a question where I referred to something by the wrong name.
Someone said I was confused / wrong, so I corrected myself and restated my question.
For some 10 minutes they just kept dogpiling on the use of the wrong term.
Never a bunch a stupider people have I met than LessWrong people.
50 replies arguing about how you can simplify your for() loop syntax and not one reply with an actual answer.
A good name might be rational Altruism because in practice these people are from the rationalist movement and doing Altruism, or what they feel is Altruism. But the "rationalist" title suffers from similar problems.
They might have lost the plot somewhere along the line, but the effective altruism movement had some good ideas.
Color me unconvinced. This will work for some situations. At this point, it's well known enough that it's a target that has ceased to be a good measure (Goodhart's Law).
The usual way to look at this is to look at the percentage of donations spent on administrative costs. This makes two large assumptions: (1) administrative costs have zero benefit, and (2) non-administrative costs have 100% benefit. Both are wildly wrong.
A simple counterexample: you're going to solve hunger. So you take donations, skim 0.0000001% off the top for your time because "I'm maximizing benefit, baby!", and use the rest to purchase bananas. You dump those bananas in a pile in the middle of a homeless encampment.
There are so many problems with this, but I'll stick with the simplest: in 2 weeks, you have a pile of rotten bananas and everyone is starving again. It would have been better to store some of the bananas and give them out over time, which requires space and maybe even cooling to hold inventory, which cost money, and that's money that is not directly fixing the problem.
There are so many examples of feel-good world saving that end up destroying communities and cultures, fostering dependence, promoting corruption, propping up the institutions that causing the problem, etc.
Another analogy: you make a billion dollars and put it in a trust for your grandchild to inherit the full sum when they turn 16. Your efficiency measure is at 100%! What could possibly go wrong? Could someone improve the outcome by, you know, administering the trust for you?
Smart administration can (but does not have to) increase effectiveness. Using this magical "how much of each dollar... ends up being used to fix some problem" metric is going to encourage ineffective charities and deceptive accounting.
As someone who has occasionally given money to charities for homelessness and the like I don't really expect it to fix much. More the thought that counts.
They think that the key to scientific thinking is to forego the moral limitations, not to study and learn. As soon as you're free from the shackles of tradition you become 100% rational and therefore 100% correct.
Like, I'm sure there are people who approximately match the description you're giving here. But I've spent a lot of time around flesh-and-blood rationalists and EAs, and they violently diverge from the account you give here.
The key to scientific thinking is empiricism and rationalism. Some people in EA and lesswrong extend this to moral reasoning, but utilitarianism is not a pillar of these communities.
On the other hand, maybe that is some kind of fallacy itself. I almost want to say that "scientific thinking" should be called something else. The main issue being the lack of experiment. Using the word "science" without experiment leads to all sorts of nonsense.
A word that means "scientific thinking is much as possible without experiment" would at least embedded a dose of skepticism in the process.
The Achilles heel of rationalism is the descent into modeling complete nonsense. I should give lesswrong another chance I suppose because that would sum up my experience so far, empirically.
EA to me seems like obvious self serving nonsense. Hiding something in the obvious to avoid detection.
In reality, they're simply lay people who synthesize a lot of garbage they find on the Internet into overly verbose pseudo-intellectual blog posts filled with both the factual inaccuracies of their source material and new factual inaccuracies that they invent from whole cloth.
I still think there's a lot to learn from those articles for most folks uninvolved in this area, even if some of their immediate optimism has additional complications.
I think what I mostly took away is a combination of technologies is likely to dramatically change how we have babies in the future.
1. We'll make sperm/egg from skin cells. This has already been done in mice[1], so it is not science fiction to do it in people.
2. When we're able to do this inexpensively, we could create virtually unlimited embryos. We can then select the embryos that have the most optimal traits. Initially, this may be simple things like not choosing embryos with certain genes that give higher risk of certain diseases.
This may involve selecting traits like intelligence and height (there are already companies that offer this embryo selection capability [2]).
3. Instead of creating a lot of embryos and selecting the best ones, we could instead create just one embryo and edit the DNA of that embryo, which has already been done in humans [3]. Alternatively, we could edit the DNA of the sperm/egg prior to creating the embryo.
The fact that none of this is science fiction is just wild. All of these steps have already been done in animals or people. Buckle up, the future is going to be wild.
[1] https://www.npr.org/sections/health-shots/2023/05/27/1177191...
[2] https://www.theguardian.com/science/2024/oct/18/us-startup-c...
[3] https://www.science.org/content/article/chinese-scientist-wh...
Eventually this will be the outcome of our species to edit the gametes themselves. The issue to overcome for this again won’t be technological as that is pretty much solved but getting people over their own “ick” factor.
>>>Eventually this will be the outcome of our species to edit the gametes themselves. The issue to overcome for this again won’t be technological as that is pretty much solved but getting people over their own “ick” factor. This is a new fear unlocked, as this will be like another cosmetic surgery procedure, which from my minimal understanding does not affect DNA that is delivered to offsprings - that could be changed but require a lot more work, but like you mentioned - it is easier to do before fertilization :). It is catch22 situation rn.
Probably requires getting investors over their profit incentive first, why treat a heritable disease for the offspring if you can charge them on a per person basis?
How to avoid having only parts of the liver with the new DNA, and some other parts with the old DNA? Like a chimeric liver - isn't this something bad?
- how further can we push this to make the best, most optimized human?
- what are moral implication of this?
- what are the side effects / downsides?
What gets harder are polygenic traits that even today we don’t have great data on what are the causal alleles. But that is also not a technological limitation either but a statistical one from insufficient sampling of these polygenic phenotypes.
There are lots of hereditary illnesses and conditions that could probably be tweaked with DNA editing, if we can identify the responsible genes. If someone can cure male pattern baldness they’ll be rich.
Really incredible story and I'd love to know the process for receiving this, for example FDA approval etc. It's nice to see such in-your-face results from Federal funding programs. Without being political, it's sometimes hard for regular people to appreciate just how much good actually comes out of Federal Funding. There was another thread where someone even said something along the lines of : "Well during war things get done faster" . This simply isn't true. It might be done louder but Federal Funding never stopped pushing things forward.
"The implications of the treatment go far beyond treating KJ, said Dr. Peter Marks, who was the Food and Drug Administration official overseeing gene-therapy regulation until he recently resigned over disagreements with Robert F. Kennedy Jr., the secretary of health and human services."
"But KJ’s treatment — which built on decades of federally funded research"
"The result “is a triumph for the American peoples’ investment in biomedical research,” Dr. Urnov said."
"The researchers emphasized the role government funding played in the development."
"The work, they said, began decades ago with federal funding for basic research on bacterial immune systems. That led eventually, with more federal support, to the discovery of CRISPR. Federal investment in sequencing the human genome made it possible to identify KJ’s mutation. U.S. funding supported Dr. Liu’s lab and its editing discovery. A federal program to study gene editing supported Dr. Musunuru’s research. Going along in parallel was federally funded work that led to an understanding of KJ’s disease."
"“I don’t think this could have happened in any country other than the U.S.,” Dr. Urnov said."
This is an article about federal funding of medical research with a cute baby as the human interest bit.
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https://innovativegenomics.org/news/first-patient-treated-wi...
It’s crazy encouraging that this worked out for this kid, and I’m somewhat shocked this treatment was approved in the US - I don’t think of us as very aggressive in areas like this. But to me, really hopeful and interesting.
As to the FDA stance, it tends to be more willing to go ahead with compassionate uses like this when it's clearly life or death.[1]
[1] https://www.statnews.com/2025/05/15/crispr-gene-editing-land... This discuss a little of the FDA stuff but not much more detail, it sounds like they did let them skip some testing.
People born with this lack the enzyme CPS1, which screws up the urea cycle and causes a build up of ammonia. Ammonia build up is bad for your nervous system.
Right off the bat, the liver receives roughly a quarter of all cardiac output, either directly or second hand from the digestive organs. Additionally, the liver has a fenestrated endothelium which, while not completely unique in the body, uniquely allows molecules like lipid nanoparticles (LNPs) to access liver cells. Finally, the liver is the site of most lipoprotein processing, and LNPs can be designed to take advantage of the existing pathways to get the gene editing mRNA into the hepatocytes. All this is to say that if you have a genetic condition that primarily effects the liver, there's a lot more hope for treatment in the near term than for others.
Good lecture on the difficulties of finding appropriate platforms for delivering gene therapies to cells for anyone interested [1]
[1] https://youtu.be/6URTjoK58Yc
mRNA vaccines are highly localized: you get a sore arm because most of it only gets taken up by muscle cells around the injection site, which spend some time producing the antigen and triggering a primary immune response (the inflammation aka the sore arm).
I can remember getting a sniffle at night and waking up fine the next morning a few times.
I think I had two doses of covid mRNA vaccine.
I have actually forgot what it is like to be sick. It almost feels like the covid vaccine gave me some kind of super immunity. I never get the flu shot either. I have not had the flu in 5 years for sure.
As for being localized it's true however after vaccine dose S proteins have been detected also in remote locations in the body because you can't make something 100% localized.
If you had an infusion that doesn't trigger immune system you could just increase the dose significantly, put it in the blood and most likely it would have reached all cells that blood reaches.
But I'm speculating a bit here.
Three interesting thing come out of it from me. First, I was on Microsoft insurance which was quite gold plated at a time, a blessing only obvious in rear-view mirror, because Childrens was quite excited to continue any number of tests. Second, the technology of all this is absolutely amazing and I am so happy that it was available to me, and it has likely gotten better. Three, I want that tech to continue to expand and current destruction up there is going to hand this torch to someone else, which makes me sad.
One of the biggest perks of working for Microsoft for a long time was their health coverage. I can't tell you the number of times I'd be doing initial paperwork for a doctor's appointment and the receptionist would be like, "Oh you have THAT insurance, we're going to do all of the tests." I've heard they since cut back on it a little, but it truly was gold plated.
What America really needs is an NHS not tied to employment or exploited by fraudsters delivering worse care for profit. Human rights shouldn't be perks of employment.
Pretty much every lab test is available in Australia if you are willing to pay for it; if they don’t have a local lab capable of running the test, they’ll send the sample overseas
The real question is whether it is covered by insurance or not, and a lot of the time the answer is “no” - I recently forked out over US$500 for genetic tests on one of our kids (which the paediatrician recommended), although the results weren’t particularly helpful (“rare variant of uncertain clinical significance”)
I know this is an issue with caesarean section. It is becoming more prevalent because those who require it are surviving, making it more likely to happen in their offspring.
>>>There are also medical procedures (PGD) to bring that chance to virtually 0%. For that one gene only. DNA is a math of sum of genes and from what I have read humans are not better than nature(which is not perfect, but very basic) at selecting best specimens of eggs and sperm, but yes - whatever they have picked - PGD might be able to root out that one single mutation, and introduce variety of other mutations or miss good genes from other combinations. So, it all depends...
You state this as a fact and I've heard it as a strong hypothesis, but I wasn't aware of much evidence to confirm it?
https://www.ncbi.nlm.nih.gov/books/NBK546707/
"If this trend continues, by 2030 the highest rates are likely to be in Eastern Asia (63%), Latin America and the Caribbean (54%), Western Asia (50%), Northern Africa (48%) Southern Europe (47%) and Australia and New Zealand (45%), the research suggests."
https://www.who.int/news/item/16-06-2021-caesarean-section-r...
Note: Coincidentally, WHO's article I've linked is lamenting that Sub-saharan Africa only had 5% cesarean due to less availability of the procedure. It is their perspective that the increase in percentages is a good thing and indicates progress, instead of being concerning. And, they find Sub-saharan Africa's low numbers concerning, instead.
Side Note: I also found lots of interesting articles which I haven't posted here, about epigenetic side effects caused by caesarean deliveries like leukemia, illnesses and other genetic issues. But, that seems out of scope for your question. You can make a quick search and find these, though.
"A female-to-female familial predisposition to caesarean section was observed. It could be caused by biologic inheritance, primarily working through maternal alleles and/or environmental factors. The results imply that both mechanisms could be important."
https://pubmed.ncbi.nlm.nih.gov/18540028/
"Large-scale epidemiological studies indeed evidence that women born by C-section are more likely to deliver by Caesarean than women born vaginally, owing primarily to genetic rather than social factors."
https://www.pnas.org/doi/10.1073/pnas.1712203114
Pretty sure their perspective is that "saving the lives of mothers and babies" indicates progress.
> While a caesarean section can be an essential and lifesaving surgery, it can put women and babies at unnecessary risk of short- and long-term health problems if performed when there is not medical need.
> Rather than recommending specific target rates, WHO underscores the importance of focusing on each woman’s unique needs in pregnancy and childbirth.
> WHO recommends some non-clinical actions that can reduce medically unnecessary use of caesarean sections, within the overall context of high quality and respectful care:
That's the potential conundrum, if it turns out to be vastly increasing the need to save those lives than in the past due to a evolutionary pressure on the gene pool. If the WHO is right and we're going to start seeing 50 - 63% increases by 2030, what's in store for the human race if this rate of expansion keeps up?
Will we reach a time when no one can be naturally born and almost our entire race has to be conceived in external gestation devices or cease to exist? And, when we reach that point will we look with concern towards Africa and wonder at how sad it is they're still conceived naturally.
Edit: I don't have the answers. I'm not sure what we should do to course correct or if we need to. But, it is definitely something that should be looked into before it is too late, if it isn't already. And, that is why I brought it up in the context of this breakthrough, to ask if we've considered similar consequences. And, if we have a way to mitigate them if that turns out to be the case.
To reply after a certain number of child comments, you have to open the comment by clicking the timestamp thing
I'm also afraid I don't understand your response. Can you elaborate?
"A female-to-female familial predisposition to caesarean section was observed. It could be caused by biologic inheritance, primarily working through maternal alleles and/or environmental factors. The results imply that both mechanisms could be important."
https://pubmed.ncbi.nlm.nih.gov/18540028/
"Large-scale epidemiological studies indeed evidence that women born by C-section are more likely to deliver by Caesarean than women born vaginally, owing primarily to genetic rather than social factors."
https://www.pnas.org/doi/10.1073/pnas.1712203114
Interesting. That makes sense. I wonder if the type of research being pursued in TFA might be helpful.
In any case, I also have to wonder whether it's necessarily a bad thing. I quoted 'natural' births earlier because... what is natural? The amount of medical knowledge and technology that go into births doesn't seem very "natural" to me, and this has advanced through the ages to where we are now - where we, rightfully so, look sadly on areas where lack of such technology and knowledge result in more preventable deaths of babies, even if their methods are more "natural"
Of course, to be honest, I'm not very familiar with the pros and cons of c-sections vs natural births - particularly when the question is whether to have a child. I suppose that, given the choice between a c-section and the alternatives, most women will opt for a c-section, and as you point out, that means their daughters likely will have to as well
So what might the solution even look like, apart from exploring the aforementioned gene-editing technology - or other technology - to prevent the genetic factor of c-sections? I would hope that "don't offer c-sections" is not a serious option. "Stop having kids" is one I'd personally suggest, but that's obviously not a sane global solution either.
It's an interesting problem I'd be curious to hear more about - as I said, I'm not very familiar with this.
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We know that infants are generally larger than 50 years ago and one of the factors which trigger birth is the inability of the mother's metabolism to support further growth of the fetus.
That, combined with the fact that all over the world availability of nutrition is much better than half a century ago points to this being the culprit.
Just because you can hit some germ-line cells in the liver, for example, doesn’t imply you’ll have good penetration into the reproductive organs.
We can’t zap people and change all their DNA at once, unless we can intervene at the point it’s just a few cells.
Hopefully not, but even then no one can say what progress will make science in the next 25 years.
Back in the 50's people thought we would be driving in flying car in 2000.
You can't compare that to gene-editing treatments, that's two completely different level.
Self driving car were always almost feasible, 20 years ago top gear made cars you could drive with controller like kids do with toy cars. We already had camera and computer, it was just a matter of raw CPU performance and software development..
We met again.
Do companies like this have a need for SWEs? Are there opportunities for a backend SWE without any background in hardware or biology?
There are two categories of software we need help with:
1. Salesforce for science. We don't have big data in terms of volume; we have big data in terms of heterogeneity. Tons of small data sets that need context to be interpreted, including measuring uncertainty. This software, often called an eLN or LIMS, is offered by expensive vendors who each have their custom, locked-in implementations. Every organization needs customization on top of this that can be developed and change with the changing direction of the bench scientists.
2. Informatics tools. Much of the heavier computational tools (bioinformatics, molecular dynamics, stats) were developed by academic labs, who don't have the training or incentives to create sustainable software. Alternatively, they are made by vendors who write software on short-term contracts, so they don't have expertise in house. Our mass spec vendor told us to put their analysis servers on our Citrix so employees could access it. Citrix! If you can convince those vendor to hire you and rewrite their software, please do.
Despite cool tools like alphafold making headlines, the software needs in drug development are more mundane. We need people who are excited to sit down with bench scientists and help them figure out how very normal tools can be applied to their work.
Of course they do. Biology and medical research can't get enough software people. But they're not as well funded as advertising or spying companies, for example, so you might have to take a significant pay cut.
I wouldn't pigeon hole yourself as a "backend engineer". Why do people do that? Software is software. The bit that matters is the core model and algorithms etc. Whether it's exposed as a web server, a CLI or just a library is a peripheral detail.
It's totally possible for a decent software engineer to learn just enough biology to get by. The limiting factor might be your interest, though. But if you have that then go for it. Get a book on genomics right now.
https://jobs.danaher.com/global/en/search-results?keywords=S...
This is SO exciting! The fact that there is a chance of a cure has absolutely made my day!
To those thinking about commercialization opportunities, these two steps seem the most labor intensive and time consuming, but also the most necessary in order to actually have confidence to inject completely customized gene editing therapy in a kid.
(Also worth highlighting for folks opposed to animal research.)
Somatic editing is becoming more common (see Casgevy) but there are technical hurdles that prevent its application to many cases.
Genuine question- how do we know that? Is it just that the edits are very improbable to accumulate in the gonads in sufficient quantities to persist? We can’t actually prevent some fraction of them from reaching other parts of the body, right?
This is _not_ the first human to be treated with a treatment under the wide umbrella of gene therapy based on their own edited genes. There probably is a more narrow first here but the technical details get lost in journalism which is a shame.
What's intriguing is not the 'custom' part, but the speed part (which permits it to be custom). Part of what makes CRISPR so powerful is that it can easily be 'adjusted' to work on different sequences based on a quick (DNA) string change - a day or two. Prior custom protein engineering would take minimum of months at full speed to 'adjust'.
That ease of manipulating DNA strings to enable rapid turnaround is similar to the difference between old-school protein based vaccines and the mRNA based vaccines. When you're manipulating 'source code' nucleic acid sequences you can move very quickly compared to manipulating the 'compiled' protein.
https://www.npr.org/2023/06/08/1178695152/china-scientist-he...