Let's say you have a running program on a computer, and you figure out a way to swap out parts of its instructions / state in RAM while it is running. What are the odds of your swap causing problems? Now, what if the program is 100 - 1000x more complex than anything you have ever managed to create.
You may not remember GameSharks, but those things did you exactly what you suggest. As do most game cheat engines. Editing the state, directly in RAM, without the program's knowledge.
The next time something tries to use whatever memory or function it overroad, it would pick up your version instead.
This is how many live-update and hot-patching systems work.
Some changes are easy and reliable; if you need to add a new condition or a few instructions, you can build your new basic block of instructions elsewhere and then atomically insert a jump to that basic block (which then jumps back to the correct post-insertion point).
Others are hard; if you need to add a new variable to some state that's being tracked, then you have to find a way to know when it's a safe time during execution to make that change, and you might have had to wrap accesses to that state in RCU gadgets.
It takes expertise, but it's doable and satisfying when you manage it!
Biology is already probabilistic, there are things going wrong with the body all the time. Most often this affects a single cell and is corrected by programmed cell death...
I once got into a debate with a classmate in undergrad. He had seen a Ted Talk and was very worried that CRISPR was going to create a new race of designer babies. I tried to explain that even CRISPR wasn't there yet, but he was under the common misconception that CRISPR is just a text editor for the genome [1].
If we want to take the computer code analogy, CRISPR is not vim/emacs/nano/ect., it is sed -i 's///g' with greedy options on.
The 'g' option is what got the researchers here. I hypothesize that a future problem will be CRISPR targeting previous CRISPR edits since the targets are relatively conserved.
I think there are plenty of diseases where people would be willing to roll the dice on low probability unintended consequences if it meant a massive 100% probability life improvement. This research is great because it reduces our uncertainty about the former option.
That said, I wouldn't wanna be the first person to do elective CRISPR therapy for something that I don't actually need (i.e. LASIK, etc).
Somatic cell modification is relatively safe. Or rather, not existentially dangerous to the species unless both extremely widespread and extremely deleterious.
I see a whole bunch of comments here where people have misunderstood the issue.
The problem here is not that unanticipated outcomes arose from our intended fix.
The problem that the exact edit we planned isn't happening in the first place, because the search-replace tools aren't yet specific and reliable enough.
It's both. With 2 or 3 cuts, you have several pieces of DNA that recombine in whatever arrangement. So in addition to the disease not being treated, you have other issues.
When the sections are subsequently rejoined, entire gene segments may be misaligned or missing. The medical consequences are unpredictable and, in the worst case, contribute to the development of leukemia.
This is also not quite accurate. The edit is happening, but the problem is the same word appears three times in the same sentence, and our program can’t distinguish them.
Specifically, there are three copies of the gene, the active one and two inactive ones. Trying to only edit one, they ended up hitting ay least one of the others as well. That then caused misalignment and other issues for the rest of the neighborhood.
We do this because reversing what caused the defect is way out of our league, just like how most advanced drugs work. The point is you take it anyway because you likely have 2 choice.
The article covers this and I think the title is a bit too general. It is a byproduct of how CRISPR works as it targets a specific sequence. In this case the sequence is also present in areas that were non-targeted. Essentially, the sequence was not unique so the process impacted other areas in unintended ways.
Let's say you have a running program on a computer, and you figure out a way to swap out parts of its instructions / state in RAM while it is running. What are the odds of your swap causing problems? Now, what if the program is 100 - 1000x more complex than anything you have ever managed to create.
You may not remember GameSharks, but those things did you exactly what you suggest. As do most game cheat engines. Editing the state, directly in RAM, without the program's knowledge.
The next time something tries to use whatever memory or function it overroad, it would pick up your version instead.
FYI doing this to a game is illegal in Japan, which kinda makes it seem like CRISPR should also be illegal in Japan.
I think this is more like introducing and RCE into your body, since CRISPR essentially modifies your executable code?
DNA is more like configuration for your molecural factories.
This is how many live-update and hot-patching systems work.
Some changes are easy and reliable; if you need to add a new condition or a few instructions, you can build your new basic block of instructions elsewhere and then atomically insert a jump to that basic block (which then jumps back to the correct post-insertion point).
Others are hard; if you need to add a new variable to some state that's being tracked, then you have to find a way to know when it's a safe time during execution to make that change, and you might have had to wrap accesses to that state in RCU gadgets.
It takes expertise, but it's doable and satisfying when you manage it!
Biology is already probabilistic, there are things going wrong with the body all the time. Most often this affects a single cell and is corrected by programmed cell death...
I once got into a debate with a classmate in undergrad. He had seen a Ted Talk and was very worried that CRISPR was going to create a new race of designer babies. I tried to explain that even CRISPR wasn't there yet, but he was under the common misconception that CRISPR is just a text editor for the genome [1].
If we want to take the computer code analogy, CRISPR is not vim/emacs/nano/ect., it is sed -i 's///g' with greedy options on.
The 'g' option is what got the researchers here. I hypothesize that a future problem will be CRISPR targeting previous CRISPR edits since the targets are relatively conserved.
[1]: https://xkcd.com/1823/
We should steer clear of modifying DNA directly until our understanding of biology is much much better.
For now, I think targeting RNA as an intermediate solution is the right approach.
I think there are plenty of diseases where people would be willing to roll the dice on low probability unintended consequences if it meant a massive 100% probability life improvement. This research is great because it reduces our uncertainty about the former option.
That said, I wouldn't wanna be the first person to do elective CRISPR therapy for something that I don't actually need (i.e. LASIK, etc).
Somatic cell modification is relatively safe. Or rather, not existentially dangerous to the species unless both extremely widespread and extremely deleterious.
I see a whole bunch of comments here where people have misunderstood the issue.
The problem here is not that unanticipated outcomes arose from our intended fix.
The problem that the exact edit we planned isn't happening in the first place, because the search-replace tools aren't yet specific and reliable enough.
It's both. With 2 or 3 cuts, you have several pieces of DNA that recombine in whatever arrangement. So in addition to the disease not being treated, you have other issues.
When the sections are subsequently rejoined, entire gene segments may be misaligned or missing. The medical consequences are unpredictable and, in the worst case, contribute to the development of leukemia.
This is also not quite accurate. The edit is happening, but the problem is the same word appears three times in the same sentence, and our program can’t distinguish them.
Specifically, there are three copies of the gene, the active one and two inactive ones. Trying to only edit one, they ended up hitting ay least one of the others as well. That then caused misalignment and other issues for the rest of the neighborhood.
The genetic version of the Clbuttic Mistake?
https://thedailywtf.com/articles/The-Clbuttic-Mistake-
We do this because reversing what caused the defect is way out of our league, just like how most advanced drugs work. The point is you take it anyway because you likely have 2 choice.
They have a targeted DNA edit that will fix the defect. They can't apply it cleanly.
Reversing the cause would require something nonsensical like editing their ancestor's DNA before they were born.
In mice?
Does it matter which CRISPR or CRISPR-like method is applied; or is there in general a dynamic response to gene editing in DNA/RNA?
The article covers this and I think the title is a bit too general. It is a byproduct of how CRISPR works as it targets a specific sequence. In this case the sequence is also present in areas that were non-targeted. Essentially, the sequence was not unique so the process impacted other areas in unintended ways.
ScholarlyArticle: "Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements" (2024) https://www.nature.com/articles/s42003-024-06959-z
Changing code you don't understand can have effects you did not intend.
Who would have expected that?
They are more or less exactly describing the change they are making, indicating they do understand the code, they just can't edit it cleanly.