I worked on a project many years ago to do RNA import into yeast mitochondria (and then hopefully reverse transcribe there). Didn't work, and a lot of the info on RNA import into the mitochondria is... suspect.
Mitochondria engineering is just actually tough. 30 years and no new protocols for getting DNA in there :(
I've been reading a lot about biochemistry lately and it's actually insane how complicated all of life is. The idea that we can edit genes at all is a miracle and I think most software engineers significantly underestimate how hard it would be to make meaningful changes to our bodies through gene editing.
I'm definitely outside my wheelhouse but I've been thinking about this lately.
I heard that CRISPR can only cut segments that match a pattern, so if there are other genes between the ends that are cut, then those are lost as well. So to do a proper substitution, we'd need to sequence the patient's genes between the cuts, and possibly the whole rest of their genome, to make sure that any patterns don't appear anywhere else, so that nothing important is removed elsewhere.
That sounds insurmountable, but it may not be. Human beings basically all have nearly identical DNA, so maybe we can just derive someone's diff from a known DNA sample. If I ever won the internet lottery, that's the sort of tool that I would want to invest in.
Then we probably need more vectors to get CRISPR where it needs to go. That sounds like more of an engineering challenge to me than having to invent something new. Or at least, the number of vectors found might correlate with R&D funding.
It's not that hard for me to imagine getting the recipe figured out to the point that it's 100% reliable and can even be delivered to specific parts of the body with a certain frequency of light, for example.
Then come up with an iterative process, probably using AI, to catalog and repair all major genetic disorders.
I don't see too much mystery there, even if the final recipes seem byzantine to human understanding. But I wanted to be a genetic engineer before I got into computers when I was 12, so I've had a long time to think about it. If AI eats the programming world like it looks like it's going to, maybe we can find work in biotech. Then it's probably 5-10 years before gene editing is a solved problem.
> if there are other genes between the ends that are cut
I think what you're saying is that if two sites on the same chromosome are cut, then everything in between is deleted. However, this isn't going to happen in practice. DNA repair systems will rejoin the cut DNA ends rapidly, just erroneously (with maybe a few dozen missing/incorrect bases typically). If the cut site is in the protein coding region, it will usually disrupt the sequence to make the protein nonfunctional. Sometimes this is the desired effect, but for most gene therapies you'll probably use base or prime editing, which don't create double strand breaks.
> we'd need to sequence the patient's genes...to make sure that any patterns don't appear anywhere else
While sequencing an individual patient's genome isn't going to happen in practice, the FDA does require gene editing companies to do in silico off-target prediction, where you scan the genome for sites that have similar sequences to the target. You then have to show that none of the off-targets are in dangerous regions (e.g. DNA repair genes), and also show experimentally whether those sites are cut at all (they usually aren't, fortunately, as there are thousands within reasonable thresholds).
The reason you don't need to sequence individual patients is because you just assume that any patient could have any variant that has ever been catalogued (there are databases with thousands of individuals and the differences between them and the reference genome). You then have to show that none of those variants could induce a new target in a dangerous region.
> then come up with an iterative process, probably using AI, to catalog and repair all major genetic disorders.
I don't know what AI would do for you here. Figuring out the change you need to make to revert a genetic disorder is trivial. The hard part is making it safe and effective, and proving to regulators that it's safe and effective.
> Then it's probably 5-10 years before gene editing is a solved problem.
Not even close. Ironically, while the technologies are pretty good in general, every edit requires a ton of engineering work. CRISPR systems are notoriously idiosyncratic - they might edit one target in 80% of cells, and 0% at another target, for no apparent reason. There are definitely open problems with base and prime editing, and those will probably get more-or-less solved in 5-10 years, but I'm reasonably sure there will be genetic disorders for which there is no treatment for decades.
It doesn't really. The START and STOP codons define clear cut frames for your cells to use. Think of your DNA like ECC memory. There's a bunch of extra stuff in there which makes it suitable for use as a memory storage. It has nothing to do with the actual replicated genes and their associated proteins or the role of those within the body.
The really cool part about that storage is it is environmentally sensitive. So as the environment changes around your DNA it's shape slightly changes and so the available START sites also change which alters the types and numbers of genes that are copied for use.
Biology isn't one system it's dozens all stacked and layered on top of each other. It's like trying to understand computing by watching what individual electrons do. Of course it looks messy. On the larger scale it's far more elegant.
start and stop codons are not as clear cut as you're implying (there are often several start sites), and variable splicing adds a bunch more stochasticity.
There are also 6 potential open reading frames in any span of DNA. 3 phases and two directions. You're looking at it backwards though. The fact that there are options means the DNA can have the same meaning but a different electrochemical signature. It's a structural memory. It's both your genes and the necessary gradient to cause them to arrange in your chromosomes correctly.
I'm not here to represent the modern DNA research perspective. You seem to have adequate access to that already. I'm a programmer. If that means you must discount my point of view entirely then so be it.
I read a book about the immune system and it’s actually insane how much tech debt there is in there. We have several systems, each one built a hundred million years after the previous one. Each one targets the kind of threats that were prevalent then but are still there because they haven’t completely disappeared. So much complexity, and systems can go haywire so easily - autoimmune diseases, allergic reactions and so on.
And yet, like a startup that found product market fit with a garbage tech stack, this pile of jenga spaghetti is still going strong. Complexity doesn’t matter, people dying because they looked at a peanut doesn’t matter - ultimately this spaghetti works well enough to get humans to where we are today.
Immune: A Journey Into the Mysterious System That Keeps You Alive By Philipp Dettmer. If you’ve heard of the Kurzgesagt channel on YouTube, it’s very similar in style.
Growing new appendages is clearly much more involved, but a Youtuber was able to give themselves lactose tolerance for a couple of months (they were lactose intolerant before). Assuming it wasn't faked for views, and that we are what we eat, that suggests other modifications to gut bateria aren't inconceivably far off.
My understanding is that lactose tolerance is a particularly interesting case because lactose tolerance is in fact the mutation and lactose intolerance is the "default". It's just that for historical reasons lactose tolerance obviously conferred an advantage in Europe in particular which is why the mutation persisted. That's why around 40% of the global population are lactose tolerant and intolerance is the global norm.
If we're thinking about the same youtuber, I found that experimental design to be really poor. They said they were lactose intolerant as a child, but they didn't confirm that they still were (decades?) later. I was lactose intolerant until I was six and then it just resolved on its own (perhaps this wasn't even lactose intolerance but a reaction to something associated with lactose).
What they should have done was eat a pizza before the treatment, gotten sick, then taken the treatment and shown that the same pizza had no effect afterwards.
Considering that there aren’t any mammals that can regrow appendages, chances are adding an appendage would be impossible with gene editing because it would require editing both the mother and offspring to support novel embryonic development.
I seem to think that human children can regrow the tips of their finger if it is cut off (I think the nail is ok, not the joint) though I don't know where I learned that, perhaps a first aid course. I've never tried it though.
That is correct, as long as the injury doesn’t take out the nail bed. That implies that there is some sort of growth factor involved with the nail bed as a signaling center, but regrown finger tips are a very simple case compared to actual appendages.
Finger tips are mostly fatty soft tissue minus the muscle, which is known to regenerate. Stuff like nerves are a completely different issue and children who regrow finger tips usually lose finer sensory input like two point discrimination.
Recently have been reading the Gene by Mukherjee. I'm amazed at what had been accomplished in the mid 20th Century. A lot of what still seems crazy now was done already albeit in small scale.
Or a wicked disease state like Huntington's that causes your DNA to slip.
Simple failures with catostrophic outcomes are much more likely than rewiring and restarting all of the developmental program across huge cell and tissue populations.
It would be more likely to grow transplant tissue exogenously. It's far safer than using the body as a test tube.
These gene editing techniques are used to fix simple (typically one cause) genetic diseases. Not reengineer live organisms "in flight".
I don't like to be alarmist, but some of this is a little scary, IMO. Small changes in a society can have massive impacts over generations. If you look at what happened to experiments with feeding house cats an altered diet in just a few generations. People are already eating a lot of things that wouldn't even be considered food a couple centuries ago, and maybe still shouldn't be.
We have a lot of increasing hormone production issues in western society already, I'm not sure that fiddling with things further is a real solution here without risking a lot of damage to society as a whole.
The amount of change that has happened just because of The Internet, and the speed of those changes is already too fast for us to cope with. We haven't even properly coped with that single change as a society and things are just accelerating...
This is quite close to the ideas of Michael Levin, a somewhat famous biologist from Tufts. The goal of his research is a "biological compiler", where you would just enter how many tails, legs and eyes you want a creature to have and hey presto.
He doesn't want to reach this by making edits in DNA, though. He is trying to simply temporarily "activate" the dormant DNA patterns for growing an ear, that were once active in the embryonal phase of the organism, in an adult organism and in a different location. His work indicates that using a correct electrochemical pattern can do this, at least in simpler organisms. He already produced some two-and three-headed worms, tadpoles with five appendages and three eyes etc. IDK how his recent work on mammals is progressing.
Maybe I'm just stupid, but I'm seeing the typical "fade-out" at the bottom of the article, followed by a subscription-wall, suggesting more of the content is behind this gate.
Tho, maybe the "Making the edit" infographic is really the bottom of the article...
We've known TALENs work for years. For example - https://pmc.ncbi.nlm.nih.gov/articles/PMC4817924/ - from 2015
I worked on a project many years ago to do RNA import into yeast mitochondria (and then hopefully reverse transcribe there). Didn't work, and a lot of the info on RNA import into the mitochondria is... suspect.
Mitochondria engineering is just actually tough. 30 years and no new protocols for getting DNA in there :(
Imagine the future - vibe coding own DNA.
"Hey ChatGPT, I need third ear. Make it grow in two months."
I've been reading a lot about biochemistry lately and it's actually insane how complicated all of life is. The idea that we can edit genes at all is a miracle and I think most software engineers significantly underestimate how hard it would be to make meaningful changes to our bodies through gene editing.
I'm definitely outside my wheelhouse but I've been thinking about this lately.
I heard that CRISPR can only cut segments that match a pattern, so if there are other genes between the ends that are cut, then those are lost as well. So to do a proper substitution, we'd need to sequence the patient's genes between the cuts, and possibly the whole rest of their genome, to make sure that any patterns don't appear anywhere else, so that nothing important is removed elsewhere.
That sounds insurmountable, but it may not be. Human beings basically all have nearly identical DNA, so maybe we can just derive someone's diff from a known DNA sample. If I ever won the internet lottery, that's the sort of tool that I would want to invest in.
Then we probably need more vectors to get CRISPR where it needs to go. That sounds like more of an engineering challenge to me than having to invent something new. Or at least, the number of vectors found might correlate with R&D funding.
It's not that hard for me to imagine getting the recipe figured out to the point that it's 100% reliable and can even be delivered to specific parts of the body with a certain frequency of light, for example.
Then come up with an iterative process, probably using AI, to catalog and repair all major genetic disorders.
I don't see too much mystery there, even if the final recipes seem byzantine to human understanding. But I wanted to be a genetic engineer before I got into computers when I was 12, so I've had a long time to think about it. If AI eats the programming world like it looks like it's going to, maybe we can find work in biotech. Then it's probably 5-10 years before gene editing is a solved problem.
Many misconceptions here, let's clear them up:
> if there are other genes between the ends that are cut
I think what you're saying is that if two sites on the same chromosome are cut, then everything in between is deleted. However, this isn't going to happen in practice. DNA repair systems will rejoin the cut DNA ends rapidly, just erroneously (with maybe a few dozen missing/incorrect bases typically). If the cut site is in the protein coding region, it will usually disrupt the sequence to make the protein nonfunctional. Sometimes this is the desired effect, but for most gene therapies you'll probably use base or prime editing, which don't create double strand breaks.
> we'd need to sequence the patient's genes...to make sure that any patterns don't appear anywhere else
While sequencing an individual patient's genome isn't going to happen in practice, the FDA does require gene editing companies to do in silico off-target prediction, where you scan the genome for sites that have similar sequences to the target. You then have to show that none of the off-targets are in dangerous regions (e.g. DNA repair genes), and also show experimentally whether those sites are cut at all (they usually aren't, fortunately, as there are thousands within reasonable thresholds).
The reason you don't need to sequence individual patients is because you just assume that any patient could have any variant that has ever been catalogued (there are databases with thousands of individuals and the differences between them and the reference genome). You then have to show that none of those variants could induce a new target in a dangerous region.
> then come up with an iterative process, probably using AI, to catalog and repair all major genetic disorders.
I don't know what AI would do for you here. Figuring out the change you need to make to revert a genetic disorder is trivial. The hard part is making it safe and effective, and proving to regulators that it's safe and effective.
> Then it's probably 5-10 years before gene editing is a solved problem.
Not even close. Ironically, while the technologies are pretty good in general, every edit requires a ton of engineering work. CRISPR systems are notoriously idiosyncratic - they might edit one target in 80% of cells, and 0% at another target, for no apparent reason. There are definitely open problems with base and prime editing, and those will probably get more-or-less solved in 5-10 years, but I'm reasonably sure there will be genetic disorders for which there is no treatment for decades.
It doesn't help that the one approved therapy isn't really making much money: https://www.biopharmadive.com/news/sickle-cell-gene-therapy-...
See also: https://blog.genesmindsmachines.com/p/we-still-cant-predict-...
Unfortunately biology only does spaghetti code.
It doesn't really. The START and STOP codons define clear cut frames for your cells to use. Think of your DNA like ECC memory. There's a bunch of extra stuff in there which makes it suitable for use as a memory storage. It has nothing to do with the actual replicated genes and their associated proteins or the role of those within the body.
The really cool part about that storage is it is environmentally sensitive. So as the environment changes around your DNA it's shape slightly changes and so the available START sites also change which alters the types and numbers of genes that are copied for use.
Biology isn't one system it's dozens all stacked and layered on top of each other. It's like trying to understand computing by watching what individual electrons do. Of course it looks messy. On the larger scale it's far more elegant.
start and stop codons are not as clear cut as you're implying (there are often several start sites), and variable splicing adds a bunch more stochasticity.
There are also 6 potential open reading frames in any span of DNA. 3 phases and two directions. You're looking at it backwards though. The fact that there are options means the DNA can have the same meaning but a different electrochemical signature. It's a structural memory. It's both your genes and the necessary gradient to cause them to arrange in your chromosomes correctly.
You call it stochastic. I call it scaffolding.
What you're saying makes absolutely zero sense from a modern DNA research perspective.
I'm not here to represent the modern DNA research perspective. You seem to have adequate access to that already. I'm a programmer. If that means you must discount my point of view entirely then so be it.
I read a book about the immune system and it’s actually insane how much tech debt there is in there. We have several systems, each one built a hundred million years after the previous one. Each one targets the kind of threats that were prevalent then but are still there because they haven’t completely disappeared. So much complexity, and systems can go haywire so easily - autoimmune diseases, allergic reactions and so on.
And yet, like a startup that found product market fit with a garbage tech stack, this pile of jenga spaghetti is still going strong. Complexity doesn’t matter, people dying because they looked at a peanut doesn’t matter - ultimately this spaghetti works well enough to get humans to where we are today.
Great comment, which book did you read?
Immune: A Journey Into the Mysterious System That Keeps You Alive By Philipp Dettmer. If you’ve heard of the Kurzgesagt channel on YouTube, it’s very similar in style.
https://www.philippdettmer.net/immune
We just haven't found God's IDE yet
Maybe this: https://teselagen.com/
Nice list here: https://github.com/davidliwei/awesome-CRISPR
from primordial_chaos import Universe
# TODO: This is a complete hack that needs to be refactored, but it works for now.
def quantum_physics() -> Universe:
well, if we look at in-memory processes or kernel, or on data on HDD disk tracks, it's kinda also awfully resembles spaghetti :)
Growing new appendages is clearly much more involved, but a Youtuber was able to give themselves lactose tolerance for a couple of months (they were lactose intolerant before). Assuming it wasn't faked for views, and that we are what we eat, that suggests other modifications to gut bateria aren't inconceivably far off.
My understanding is that lactose tolerance is a particularly interesting case because lactose tolerance is in fact the mutation and lactose intolerance is the "default". It's just that for historical reasons lactose tolerance obviously conferred an advantage in Europe in particular which is why the mutation persisted. That's why around 40% of the global population are lactose tolerant and intolerance is the global norm.
https://en.wikipedia.org/wiki/Lactase_persistence
If we're thinking about the same youtuber, I found that experimental design to be really poor. They said they were lactose intolerant as a child, but they didn't confirm that they still were (decades?) later. I was lactose intolerant until I was six and then it just resolved on its own (perhaps this wasn't even lactose intolerance but a reaction to something associated with lactose).
What they should have done was eat a pizza before the treatment, gotten sick, then taken the treatment and shown that the same pizza had no effect afterwards.
Considering that there aren’t any mammals that can regrow appendages, chances are adding an appendage would be impossible with gene editing because it would require editing both the mother and offspring to support novel embryonic development.
I seem to think that human children can regrow the tips of their finger if it is cut off (I think the nail is ok, not the joint) though I don't know where I learned that, perhaps a first aid course. I've never tried it though.
That is correct, as long as the injury doesn’t take out the nail bed. That implies that there is some sort of growth factor involved with the nail bed as a signaling center, but regrown finger tips are a very simple case compared to actual appendages.
Finger tips are mostly fatty soft tissue minus the muscle, which is known to regenerate. Stuff like nerves are a completely different issue and children who regrow finger tips usually lose finer sensory input like two point discrimination.
Recently have been reading the Gene by Mukherjee. I'm amazed at what had been accomplished in the mid 20th Century. A lot of what still seems crazy now was done already albeit in small scale.
And then when it gets it wrong and you ask why it grew a nose instead of an ear: "You're absolutely right! I can fix this!"
You mean cancer.
Or a wicked disease state like Huntington's that causes your DNA to slip.
Simple failures with catostrophic outcomes are much more likely than rewiring and restarting all of the developmental program across huge cell and tissue populations.
It would be more likely to grow transplant tissue exogenously. It's far safer than using the body as a test tube.
These gene editing techniques are used to fix simple (typically one cause) genetic diseases. Not reengineer live organisms "in flight".
Your liver is covered with ears and they’ve started spreading to your lymph nodes.
I don't like to be alarmist, but some of this is a little scary, IMO. Small changes in a society can have massive impacts over generations. If you look at what happened to experiments with feeding house cats an altered diet in just a few generations. People are already eating a lot of things that wouldn't even be considered food a couple centuries ago, and maybe still shouldn't be.
We have a lot of increasing hormone production issues in western society already, I'm not sure that fiddling with things further is a real solution here without risking a lot of damage to society as a whole.
> If you look at what happened to experiments with feeding house cats an altered diet in just a few generations.
Can you point to a reference?
https://drsurinderarora.com/articles/f/nutrition-for-dentiti...
Identifying unmodified human in the future is necessary.
The amount of change that has happened just because of The Internet, and the speed of those changes is already too fast for us to cope with. We haven't even properly coped with that single change as a society and things are just accelerating...
Now we "just" need a CRISPR-MCP server :p
On the public internet
This is quite close to the ideas of Michael Levin, a somewhat famous biologist from Tufts. The goal of his research is a "biological compiler", where you would just enter how many tails, legs and eyes you want a creature to have and hey presto.
He doesn't want to reach this by making edits in DNA, though. He is trying to simply temporarily "activate" the dormant DNA patterns for growing an ear, that were once active in the embryonal phase of the organism, in an adult organism and in a different location. His work indicates that using a correct electrochemical pattern can do this, at least in simpler organisms. He already produced some two-and three-headed worms, tadpoles with five appendages and three eyes etc. IDK how his recent work on mammals is progressing.
Take a look at Michael Levin's work: he's been able to get animals to grow eyes on their legs (or something similar), without gene manipulation, but just by messing with bioelectrical fields. Paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC3587383/?utm YouTube interview: https://youtu.be/Kpx5isuKD1c?si=RU6fztq_RexUvYif
Two months go by then suddenly three more ears appear on your head.
Damn those hallucinations!
This reminded me of the 1995 The Outer Limits episode "The New Breed".
"Hey you #$#@ remove the ear from my anus"
A nice soul have a non-paywalled version to share ?
https://www.nature.com/articles/d41586-025-03307-x.pdf
this should work?
Maybe I'm just stupid, but I'm seeing the typical "fade-out" at the bottom of the article, followed by a subscription-wall, suggesting more of the content is behind this gate. Tho, maybe the "Making the edit" infographic is really the bottom of the article...
the only current archive on archive.is also has that. Watch this space for a complete archive, hopefully:
https://archive.is/https://www.nature.com/articles/d41586-02...