[HN Gopher] Genetic repair via CRISPR can inadvertently introduc...
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Genetic repair via CRISPR can inadvertently introduce other defects
Author : amichail
Score : 87 points
Date : 2024-11-08 17:13 UTC (5 hours ago)
(HTM) web link (phys.org)
(TXT) w3m dump (phys.org)
| psadri wrote:
| 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.
| georgyo wrote:
| 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.
| 0x457 wrote:
| I think this is more like introducing and RCE into your body,
| since CRISPR essentially modifies your executable code?
| thrw42A8N wrote:
| DNA is more like configuration for your molecural
| factories.
| exe34 wrote:
| configuration is code.
| 0x457 wrote:
| speakig like a true "exe"
| thrw42A8N wrote:
| Not in this case. There is only a very restricted set of
| options and these can be interpreted in different ways by
| different machines that read it.
| hoherd wrote:
| FYI doing this to a game is illegal in Japan, which kinda
| makes it seem like CRISPR should also be illegal in Japan.
| chiffre01 wrote:
| I remember having a Game Genie, it worked sometimes. But like
| the article says. it would also make things glitchy and crash
| everything now and then.
| jncfhnb wrote:
| Not surprising. They weren't designed cheat codes. Folks
| would try stuff, sort of figure out what it did, and then
| publish it with a name.
| TrainedMonkey wrote:
| 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...
| colmmacc wrote:
| 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!
| the5avage wrote:
| Changing code you don't understand can have effects you did not
| intend.
|
| Who would have expected that?
| maxerickson wrote:
| 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.
| the5avage wrote:
| Oh, maybe I missed that we already completely understand how
| DNA works.
| maxerickson wrote:
| Yes, we do understand the mutations that we would target
| with something like crispr, where protein coding has been
| disrupted by a small error.
| westurner wrote:
| ScholarlyArticle: "Gene editing of NCF1 loci is associated with
| homologous recombination and chromosomal rearrangements" (2024)
| https://www.nature.com/articles/s42003-024-06959-z
| westurner wrote:
| 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?
| ca_tech wrote:
| 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.
| lawrenceyan wrote:
| 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.
| nharada wrote:
| 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).
| thfuran wrote:
| Somatic cell modification is relatively safe. Or rather, not
| existentially dangerous to the species unless both extremely
| widespread and extremely deleterious.
| Nasrudith wrote:
| How are we to learn how biology works better without modifying
| DNA directly? We learn through experimentation, not sitting
| upon a pedestal and pontificating for decades.
| impish9208 wrote:
| In mice?
| Terr_ wrote:
| 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.
| function_seven wrote:
| The genetic version of the Clbuttic Mistake?
|
| https://thedailywtf.com/articles/The-Clbuttic-Mistake-
| dmvdoug wrote:
| 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 the 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.
| maxerickson wrote:
| 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._
| m3kw9 wrote:
| 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.
| maxerickson wrote:
| 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.
| MillironX wrote:
| 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/
| mmcclure wrote:
| A lot of the graphics that explain how CRISPR work show this very
| careful snipping of a strand of DNA. Tiny little scissors making
| pinpoint accuracy revisions. I think that's lead to a deep
| misunderstanding for most people (including myself) on how this
| technology actually works.
|
| CRISPR is amazing, but it's still a fairly blunt tool. The
| article talks about one way: guide RNA can often bind to
| sequences that are very similar to the intended sequence, but not
| exactly, meaning it's probable that for every intended cut you're
| making several unintended ones. The "scissor" action itself, Cas9
| protein, is less like a scissor cut and more like a jagged tear,
| which can damage surrounding DNA.
|
| The repair pathways themselves are also imperfect. It's not a
| copy/paste like infographics show, it's more like emergency duct
| taping broken ends together.
|
| All of that stuff combined...Again, amazing technology, but I get
| extremely nervous when I hear people talk about introducing
| CRISPR-based gene editing into the human gene pool. The
| generational effects there are still entirely unpredictable at
| this stage, could be disastrous, and any actual paths to trying
| to roll things back would be deeply ethically fraught.
| aliasxneo wrote:
| > the generational effects there are still entirely
| unpredictable at this stage
|
| Something I've always wondered about CRISPR. It seems the legal
| case for introducing it is the freedom to perform "body
| hacking" on yourself. But, at least in this case, isn't it more
| like "generational hacking?" Maybe I am fundamentally
| misunderstanding the technology, but it's strange to think
| about what sort of protections should be put in place to
| prevent someone being born with severe defects due to messing
| with the genome.
| dghlsakjg wrote:
| I'm not sure about that...
|
| Isn't restricting people from reproducing based on their
| genetic material known as Eugenics?
| mmcclure wrote:
| This is the "ethically fraught" bit I was referencing. Once
| this genie is out of the bottle and into the gene pool,
| there's effectively no moral/ethical path to putting it
| back in.
| aliasxneo wrote:
| This certainly highlights the problem. For context, I
| wasn't suggesting eugenics, although I suppose that's one
| way to enforce things (one I would never support, anyways).
| jpalawaga wrote:
| People like to compare CRISPR as scissors or cut/copy-and-
| replace, but people should think of it more as 'find and
| replace all'.
|
| in that context, it's much more understandable why the tool has
| drawbacks.
| mmcclure wrote:
| Yeah, better analogy, but still a little flawed because that
| still makes it seem much better/precise than it is. It's
| "find and replace all" that might:
|
| - occasionally match very similar, but not exact text
|
| - will often subtly alter the text around the replacement
| area, either by deleting characters or altering others.
| albertgoeswoof wrote:
| It's more like pasting your genome into chatgpt and asking
| it to fix it
| ch1kkenm4ss4 wrote:
| No shit.
|
| I would personally love to get a gene theraphy for an inherited
| auto-immune disease, but mankind just doesn't have 'the full
| picture' - yet. So i'll stick with known treatments.
| jayyhu wrote:
| Consider a scenario where you're editing a function:
| function foo() { return a*2.1^2+0.52/2 }
|
| So you do a find-all regex "1.*5" and delete _all_ matching
| occurrences (a la CRISPER) to get: function foo()
| { return a*2.2/2 }
|
| But unbeknownst to you, the code is littered with a bunch of
| commented out versions of the same function you're trying to
| edit: /* function foo() { return a*1.5/2.1 } */
| /* function foo() { return a*1.95/2.4 } */
|
| And now those commented out versions now become:
| /* function foo() { return a*/2.1 } */ /* function foo() {
| return a*/2.4 } */
|
| And now the whole program doesn't compile anymore--or your
| patients get Leukemia. Oops.
| kps wrote:
| You can't parse DNA with regex1.
|
| 1 https://stackoverflow.com/questions/1732348/regex-match-
| open...
| abc_lisper wrote:
| Excellent point. But it works for bacteria I guess, because
| viral dna is small.
| zackmorris wrote:
| I upvoted this because it's perhaps the most important research
| being conducted currently. But the seriousness of the issue is
| misleading.
|
| CRISPR is revolutionary technology. Any side effects of its use
| require evolutionary improvements. The two are not the same.
|
| With the decades of experience we have dealing with code and
| information, as well as the arrival of AI, I wish that people
| would stop obsessing about the difficulty of solving problems.
| The difficulty is gone. All problems are solvable now, it's just
| a matter of time, effort, and a tiny fraction of the money that
| used to be required.
|
| But FUD seems to dominate these discussions. That's probably my
| biggest disappointment with, say, the rich and powerful who
| gatekeep funding and the media. It's even easier for them to
| solve these problems, or encourage healthy debate. But they seem
| to go out of their way to do the opposite. Like, if it weren't
| for wealth inequality, we could have been working on this stuff,
| and found the answers potentially years ago. I'll just never
| understand the so-called realists and how they hold us back in
| these times out of fear, which leads to false equivalence and
| generalization.
| DidYaWipe wrote:
| I wonder if there's a pattern to genes that are adjacent to the
| target ones, which is not typically found adjacent to the pseudo
| ones. In other words, can the "search term" be expanded to make
| it more selective and then take action on the target region
| within it.
| kylehotchkiss wrote:
| Of course editing genes with CRISPR can introduce other defects!
| Genetic sequences can serve multiple purposes, alternative
| splicing, polygenic traits etc. It's an exciting discovery with
| interesting repurpose applications but DNAs application is not
| just a linear read
| Dwedit wrote:
| There were some numbnuts that were calling themselves "Bio
| Hackers" and freely injecting themselves with random CRISPR
| injections. I wonder what's going to happen to them.
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