MontyCarloHall
Joined 7 years ago
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Recent submissions
Comment · 4 months ago
Comment · 4 months ago
Another data point: GitHub is extremely insistent its employees maximally use AI for internal development [0], and we’ve concomitantly seen its reliability fall off a cliff in the last year or so.
[0] https://github.com/resources/insights/ai-powered-workforce-p...
Comment · 4 months ago
I don’t prompt Claude anymore. I have loops running that prompt Claude and figuring out what to do. My job is to write loops.
— Boris Cherny, head of Claude Code
Comment · 4 months ago
Including additional guides is negligible with respect to the overall LNP capacity, which can contain a few thousand nucleotides. The CRISPR/Cas mRNA is about 5 kilobases total, and each guide is on the order of 100 bases.
Comment · 4 months ago
Sure, but my point is that convergent selective pressure across different individuals' tumors is strong enough that they independently arrive on the same resistance mechanisms to a given therapy, e.g. [0]. Just like if you performed the same bacterial antibiotic resistance experiment [1] across multiple independent trials, you'd repeatedly get the same result.
Comment · 4 months ago
In practice, you’d use multiple guides targeting multiple mutations, so that the probability of having/acquiring multiple resistance mutations abrogating every guide from binding would be infinitesimal.
Comment · 4 months ago
Even with 100% delivery efficacy, editing efficacy is nowhere near 100%. CRISPR/Cas editors will reliably detect the target sequence but will not reliably edit it in order to repair the mutant allele, whereas CRISPR/Cas12a2 will activate and destroy chromatin ~100% of the time when it detects the target.
As is often the case, it's a lot easier to indiscriminately destroy than precisely (re)build.
Comment · 4 months ago
Agreed. Assuming it's ultimately proven to work in vivo, I think the endgame of this therapy is multiple guides targeting multiple mutations along with multiple delivery mechanisms (a formulation-diverse cocktail of LNPs + eVLPs [0]?). Sure, tech like [0] is futuristic and fanciful, but so is the tech of the OP, and both will probably reach in vivo maturity around the same time.
Comment · 4 months ago
>Depending on how the LNPs are designed, would resistance also potentially cripple the cancer cells?
Yes, if the LNP could be engineered to target an essential surface receptor, which is still a very tough problem. It would also not solve the issue of the payload successfully entering the cell but being subsequently degraded.
>I've heard about drug resistance in bacteria leading to slower growth / reduced virulence. Maybe the same would occur with cancers. A drug that could effectively switch an aggressive cancer into a slow-growing one wouldn't be the worst thing.
This is essentially how treatment for chronic lymphocytic leukemia happens (hence why it's called "chronic"). People with CLL can stay on BTK inhibitors for decades, often until they die of other natural causes.
Comment · 4 months ago
>there's no "be a better/stronger cancer and spread more effectively to more hosts"
No, but there is "be a better/stronger cancer cell and don't succumb to whatever therapy is killing its neighboring cells." It's exactly akin to how dosing isolated populations of bacteria with antibiotics selects for individual cells that are resistant, which then multiply and dominate [0], just like a tumor.
Comment · 4 months ago
This would shorten the timeframe for cells to mutate and acquire resistance mechanisms, but would not address the issue of cells with preexisting (epi)genetic resistance mechanisms that would then be promptly selected for.
Comment · 4 months ago
Nonetheless, we see the exact same resistance mechanisms to the same therapies recur across individuals, e.g. [0]. Convergent evolution is a harsh mistress.
Comment · 4 months ago
The idea of using CRISPR/Cas to detect tumor-specific mutations that aren't necessarily oncogenic and then kill the cell is not a new one [0, 1, 2]. However, previous studies used Cas9, which just damages the DNA at the target site; this uses Cas12a2, which is far more destructive because it shreds the chromatin in the cell once activated by detecting the target sequence.
As with any cancer treatment, it's likely the tumor will evolve resistance. My guess is that cells will find ways to reject the lipid nanoparticles used to deliver the CRISPR/Cas mRNA and associated guide sequence(s), either via modifications to the cell surface (preventing LNP uptake) or via changes to endosomal/lysosomal pathways (causing the mRNA payload to get degraded before it has a chance to be translated into protein).
[0] https://pubmed.ncbi.nlm.nih.gov/28575452/
Comment · 4 months ago
>[B]y far the most common reason given is that the cost of living has risen to such an extent that they feel that rearing children has become unaffordable.
That's certainly a factor, though very aggressive financial incentives for parents don't seem to work very well [0, 1, 2]. Not to mention that in rich countries, educational attainment and income are negatively correlated with fertility [3]. My theory there is that people's high-powered careers provide them more self-satisfaction than having kids.
>it's the fact that they can't even afford to buy somewhere to live.
It's funny you mention this. Some friends said they weren't having a second kid because they couldn't afford a three bedroom house, not realizing that kids sharing bedrooms was the norm for middle class families until very recently. Having one bedroom per kid was a luxury just 30-40 years ago.
>I won't comment on your assertion that the freedom to watch "adult-appropriate movies on a big TV in the living room" is a more fulfilling state of being than parenthood
It's not my assertion, it's something a couple deciding to not have another kid literally told me. They missed being able to have substantial amounts of adult time, and were actively counting down the days until their only child was old enough to amuse himself for long periods of time. Having another kid would reset that clock.
[0] https://www.economist.com/europe/2026/03/19/viktor-orbans-pr...
[1] https://www.theguardian.com/world/2024/feb/28/south-korea-fe...
[2] https://worldcrunch.com/culture-society/boosting-birth-rates...
[3] https://www.oecd.org/en/publications/society-at-a-glance-202...
Instead, the whole system just shits the bed, catastrophically.