5 ms·

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

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.

lanfeust6 1y ago
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.
fragmede 1y ago
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.
- throwup238 1y ago
  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.
  - clort 1y ago
    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.
    - throwup238 1y ago
      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.
- seanhunter 1y ago
  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 https://en.wikipedia.org/wiki/Lactase_persistence
- jryb 1y ago
  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.
toasterlovin 1y ago
Unfortunately biology only does spaghetti code.
- BartjeD 1y ago
  We just haven't found God's IDE yet
  - rabf 1y ago
    Maybe this: https://teselagen.com/ https://teselagen.com/ Nice list here: https://github.com/davidliwei/awesome-CRISPR https://github.com/davidliwei/awesome-CRISPR
  - psunavy03 1y ago
    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:
- testdelacc1 1y ago
  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.
  - andy_ppp 1y ago
    Great comment, which book did you read?
    - testdelacc1 1y ago
deleted 1y ago
[deleted]
zackmorris 1y ago
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.
- jryb 1y ago
  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-slow-uptake-casgevy-lyfgenia/734938/ https://www.biopharmadive.com/news/sickle-cell-gene-therapy-... See also: https://blog.genesmindsmachines.com/p/we-still-cant-predict-much-of-anything https://blog.genesmindsmachines.com/p/we-still-cant-predict-...

lanfeust6 1y ago

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.

fragmede 1y ago

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.

throwup238 1y ago
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.
- clort 1y ago
  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.
  - throwup238 1y ago
    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.
seanhunter 1y ago
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 https://en.wikipedia.org/wiki/Lactase_persistence
jryb 1y ago
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.

toasterlovin 1y ago

Unfortunately biology only does spaghetti code.

BartjeD 1y ago
We just haven't found God's IDE yet
- rabf 1y ago
  Maybe this: https://teselagen.com/ https://teselagen.com/ Nice list here: https://github.com/davidliwei/awesome-CRISPR https://github.com/davidliwei/awesome-CRISPR
- psunavy03 1y ago
  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:
testdelacc1 1y ago
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.
- andy_ppp 1y ago
  Great comment, which book did you read?
  - testdelacc1 1y ago

deleted 1y ago

[deleted]

zackmorris 1y ago

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.

jryb 1y ago
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-slow-uptake-casgevy-lyfgenia/734938/ https://www.biopharmadive.com/news/sickle-cell-gene-therapy-... See also: https://blog.genesmindsmachines.com/p/we-still-cant-predict-much-of-anything https://blog.genesmindsmachines.com/p/we-still-cant-predict-...