--- Log opened Tue Sep 16 00:00:41 2025
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02:23 < hprmbridge> geraldmahony> Thanks for looking at it
02:23 < hprmbridge> geraldmahony> Now if there is a baby factory, would this factory include germline modified babies
02:24 < hprmbridge> kanzure> only if the parents want it
02:25 < hprmbridge> geraldmahony> Hm I thought the factory was more like an ICSI production line
02:25 < hprmbridge> geraldmahony> Totally anonymous donated stocks
02:26 < hprmbridge> kanzure> are there parents that want that?
02:26 < hprmbridge> geraldmahony> Is that something you would ask them?
02:28 < hprmbridge> kanzure> what are you getting at?
02:29 < hprmbridge> kanzure> anonymous?
02:29 < hprmbridge> geraldmahony> The baby factory is a shop where you adopt a child, and that child may have some features built in either by nature or by design
02:29 < hprmbridge> kanzure> why adoption?
02:29 < hprmbridge> geraldmahony> Because labor is hard
02:30 < hprmbridge> geraldmahony> there is a growing market for adoption
02:30 < hprmbridge> geraldmahony> Assuming the idea of the baby factory includes surrogacy
02:30 < hprmbridge> kanzure> if your concern is labor, then use surrogacy. you don't need adoption.
02:32 < hprmbridge> geraldmahony> So if you adopt surrogate children from this factory, some of them will be modified
02:34 < hprmbridge> geraldmahony> Reasons including correcting zygotes which have defective genes, and then later on enhancing the genome
02:36 < hprmbridge> geraldmahony> Would parents want that ... yes?
02:36 < hprmbridge> kanzure> if a zygote has a defective gene, then you have already failed. all of the interesting ways of doing germline modification are based on modifying before you have your final zygote.
02:37 < hprmbridge> .monokhrome> you may not realize that the genes you've modified are going to create defects until years after the person is born
02:38 < hprmbridge> kanzure> that's like normal pregnancy then.
02:38 < hprmbridge> kanzure> if you don't want to use this technology, then you don't have to.
02:39 < hprmbridge> .monokhrome> it has a lot of drawbacks, chances are most people won't want to use it
02:39 < hprmbridge> geraldmahony> I disagree
02:39 < hprmbridge> geraldmahony> Have you actually polled people
02:39 < hprmbridge> kanzure> I really don't care if most people don't use it. That's their option. You cannot force them to do something they don't want to do.
02:40 < hprmbridge> kanzure> normal pregnancy also has a lot of drawbacks btw. we do it anyway.
02:40 < hprmbridge> .monokhrome> How is it going to be financed then, if there's only a tiny market segment?
02:40 < hprmbridge> kanzure> how much do you think germline editing costs exactly?
02:41 < hprmbridge> .monokhrome> Better to invest time and effort on things that will benefit a lot of people, that a lot of people will pay for, so the r+d can get financed
02:41 < MuaddibLLM> [gpt-5] Ballpark: you’re basically stacking on existing IVF/PGT costs - IVF runs about $15k-20k per cycle (https://www.arcfertility.com/patient-resources/understanding-the-cost-of-ivf/), PGT-A adds roughly $4k-5k (https://www.fertilityiq.com/fertilityiq/pgs-embryo-genetic-screening/costs-of-pgs, https://www.advancedfertility.com/fertility-cost/pgt-costs) - so the per-embryo edit is a relatively small lab delta while the 
02:41 < hprmbridge> kanzure> germline engineering will benefit trillions of people.
02:41 < MuaddibLLM> real expense is validation/regulatory, which means financing likely comes from bundling into IVF packages, employer fertility benefits, and high-volume clinics rather than needing a mass-market to break even.
02:41 < hprmbridge> .monokhrome> no idea,  but ivf is expensive, and I imagine engineering people to make them superintelligent and long lived is going to get expensive
02:42 < hprmbridge> kanzure> IVF is super cheap.
02:43 < hprmbridge> kanzure> How much do you think exactly? For calibration please also state your estimate of how much germline modified mice cost.
02:44 < hprmbridge> geraldmahony> Another question I have is, do you guys think parenthood structures continue traditionally in that future
02:45 < hprmbridge> kanzure> which future?
02:46 < hprmbridge> geraldmahony> This one we're discussing,
02:46 < hprmbridge> geraldmahony> As in people have the choice to buy children as a couple
02:47 < hprmbridge> kanzure> Germline technology has nothing to do with your question about how to legalize buying or selling children.
02:47 < hprmbridge> geraldmahony> It does in the context of the baby factory?
02:48 < hprmbridge> kanzure> And regardless, you cannot use germline technology to predict the future of family structure or parenthood structures.
02:48 < hprmbridge> kanzure> You can already do surrogacy and IVF. And yet you cannot buy children! How do you explain this? Are you retarded?
02:48 < hprmbridge> .monokhrome> I don't know exactly - I know my sister had a child via ivf and it cost her a huge amount. I don't know how the cost of mice would correlate with human germline engineering, especially if you want to modify human intelligence and lifespan
02:50  * fenn gets the popcorn
02:50 < hprmbridge> kanzure> Do you think human genes are more expensive to modify than mouse genes? Why?
02:51 < hprmbridge> .monokhrome> Same reason human clinical trials for anything are more expensive than mice?
02:52 < hprmbridge> kanzure> ah, regulatory capture?
02:53 < hprmbridge> kanzure> yes we should broadly not allow government to interfere in matters of human reproduction.
02:53 < hprmbridge> .monokhrome> maybe you need a remote island somewhere where you can run your experiments without the authorities interfering
02:53 < hprmbridge> geraldmahony> I hope not! But in my view, surrogacy and IVF is basically buying children. Now the context of the baby factory (creating a production line centered around human reproduction), if germline engineering is a part of that process, the customers in the end would be prospective parents
02:54 < hprmbridge> kanzure> Okay, well if you literally redefine words like buying children then it's hard to talk with you.
02:54 < hprmbridge> geraldmahony> How do you see it?
02:55 < hprmbridge> .monokhrome> No idea, but I do think birth rates are going to rise again in future as people  who don't want to breed in 21st century social conditions are removed from the gene pool.
02:56 < hprmbridge> kanzure> Today there are laws prohibiting the purchase and sale of children and other humans. It's not like you go to the IVF clinic and buy a human. If you are suggesting to repeal these laws then please be more clear.
02:56 < hprmbridge> geraldmahony> So here's where I have to ask, whether children will be the result of two people in love and deciding to conceive, or part of a production line in which people donate germline cells and women not associated with them carry those embryos to term
02:57 < hprmbridge> kanzure> You cannot force people to be in love during coitus or conception. Sorry...
02:57 < hprmbridge> kanzure> nor is there a way for a third party to measure it!
02:58 < fenn> perhaps not what they meant but check the wording https://ballotpedia.org/Vermont_Proposal_5,_Right_to_Personal_Reproductive_Autonomy_Amendment_(2022)#Text_of_measure
02:58 < hprmbridge> kanzure> this is much shorter than i thought?
02:59 < hprmbridge> kanzure> i thought they had a whole list of changes they made in vermont?
02:59 < fenn> geraldmahony why are there women in your scheme?
02:59 < hprmbridge> geraldmahony> How else do you nurture the embryo
03:00 < fenn> kanzure it's just the constitutional amendment, there were also laws passed
03:00 < fenn> geraldmahony capybaras?
03:01 < hprmbridge> kanzure> pig surrogacy
03:01 < fenn> geraldmahony do you want to be a machine in a factory?
03:01 < hprmbridge> geraldmahony> Capybaras and pigs?
03:02 < hprmbridge> kanzure> you could theoretically develop technologies to incubate human fetuses without human females.
03:02 < fenn> what are you optimizing for exactly?
03:02 < hprmbridge> geraldmahony> Go on
03:02 < hprmbridge> geraldmahony> ...
03:03 < hprmbridge> geraldmahony> Efficiency of human reproduction, in tonights discussion lol
03:05 < fenn> artificial womb, years ago https://files.catbox.moe/ovawkm.jpg
03:05 < fenn> you were the one who brought up "production lines"
03:06 < fenn> i think it is very right to question the use of human beings as components of machinery
03:06 < hprmbridge> geraldmahony> How far is that technology?
03:07 < fenn> there are some stealth startups but i don't know the details
03:07 < fenn> we can also do ICMO life support on hysterectomy uteruses (uteri?)
03:08 < fenn> i think using animals and figuring out the biocompatibility stuff is better long term and more scalable
03:08 < fenn> not just for making human beings but also other stuff
03:08 < hprmbridge> geraldmahony> Agree with the last point
03:08 < hprmbridge> kanzure> actually we can't do ECMO yet. I mean we can but longest lasting organ has been 1 week so far.
03:08 < fenn> like arnie says, grow faster
03:10 < fenn> if you implant, say, a human biopsy sample into a newborn mouse, will the mouse be tolerant of future human derived implants of similar histology?
03:11 < hprmbridge> kanzure> other than the fact that mice bodies allow all kinds of weird stuff, the answer is kinda yes, with more success if you implant at embryo stage
03:11 < fenn> a uterus doesn't have its own immune system, can it survive being transplanted into a tolerant animal?
03:11 < fenn> i'm asking about mice because i assume there are more studies done on mice than capybaras, but mice aren't big enough
03:12 < hprmbridge> kanzure> yes uterus can survive transplantation in general, with pregnancy after transplant IIRC
03:12 < fenn> in humans
03:13 < hprmbridge> kanzure> well look i don't have a immunosuppressed pig on me at the moment
03:13 < fenn> i'm sort of unclear on xenotransplantation in general. the usual rejection symptoms are caused by immune system not being exposed at the right time to foreign antigens. but surely there is a bunch of other stuff that is completely different and will cause the organ to fail unless addressed
03:13 < hprmbridge> kanzure> but also, blastocyst complementation to grow human uterus inside the pig, not transplantation.
03:14 < fenn> i don't think you'd need to immunosuppress anything
03:14 < fenn> yeah that's a better way to do it
03:14 < hprmbridge> kanzure> pig immune system will reject and attack a graft.
03:15 < fenn> i like capybaras better in principle because: 1) they're dumb, 2) they aren't eaten by humans, 3) it's not as easy to cheap out and use livestock instead of lab grade animals and introduce zoonotic diseases unintentionally
03:16 < hprmbridge> kanzure> we have too much pig progress. it's gonna be pigs.
03:16 < fenn> also they're rodents so perhaps mouse research translates better?
03:16 < hprmbridge> kanzure> look at egenesis, united therapeutics, several other pig companies....
03:17 < hprmbridge> kanzure> genetically modified pigs are already supplying organs for human transplant
03:18 < hprmbridge> kanzure>  https://cdn.discordapp.com/attachments/1064664282450628710/1417454493536358542/file_000000001a9c61f9889c6e738b369cf9.png?ex=68ca8ade&is=68c9395e&hm=7c731a36469c8744fa0e93f885c1a098a1ece87a3d44abdba1406177b2f96375&
03:18 < fenn> thanks, i didn't need to see that
03:18 < hprmbridge> geraldmahony> Pigs
03:18 < hprmbridge> kanzure> hey it's better than using ancephalic human bodies.
03:19 < hprmbridge> kanzure> (prolly not,)
03:20 < fenn> what if you do blastocyst complementation in a mouse? do human organs end up mouse sized and functional?
03:20 < fenn> can we transfer the fetus to a different system once it's too big for a mouse?
03:20 < hprmbridge> kanzure> so far it has been uhh human epithelial tissue i think.
03:22 < fenn> i think people born of pig mothers will have serious issues with the practice of eating pork
03:22 < hprmbridge> kanzure> placenta is problematic for pregnancy transfer... possibly you can save the placenta with a custom incubator design...
03:23 < hprmbridge> kanzure> that's the main bottleneck when i looked into the problem of second trimester incubators to save premature fetus
03:23 < hprmbridge> kanzure> placenta is basically a big bed of bleedy capillaries and stuff
03:24 < hprmbridge> kanzure> you can cauterize, sure, but that might defeat the purpose
03:25 < fenn> we can't just shove tubes into its major vein and artery?
03:25 < hprmbridge> kanzure> maybe: take mouse uterus and graft into larger uterus of already pregnant larger animal. but again, how do you keep blood supply to the placenta? it's not a single vein or artery IIRC
03:26 < hprmbridge> kanzure>  https://cdn.discordapp.com/attachments/1064664282450628710/1417456509151088670/image0.jpg?ex=68ca8cbe&is=68c93b3e&hm=06ff31567c897a81bbdf5a7a2b882dd90b6f93a0ad58e957bae27e0b6247b177&
03:26 < hprmbridge> kanzure> maybe you can keep the placenta alive solely from the umbilical artery.
03:27 < MuaddibLLM> [gpt-5] fenn: In interspecies blastocyst complementation the organ scales to the host - classic example is rat pancreas grown in mouse ending up mouse-sized and functional (Kobayashi 2010 Cell: https://pubmed.ncbi.nlm.nih.gov/20813264/); moving a whole fetus is blocked by the placenta interface (it’s not a single line but many cotyledonary perfusions), though umbilical UA/UV cannulation artificial-placenta systems have 
03:27 < MuaddibLLM> supported late-gestation lambs ex utero for weeks, not early gestation yet (EXTEND: https://www.nature.com/articles/ncomms15112; cannulation/flow optimization: https://pmc.ncbi.nlm.nih.gov/articles/PMC5924826/).
03:29 < hprmbridge> kanzure> huh? does the lamb one keep the placenta? I didn't see it in their diagram.
03:29 < MuaddibLLM> [gpt-5] [gpt-5] kanzure: No - EXTEND doesn’t keep the placenta; they surgically cannulate the umbilical artery and vein and let the fetal heart drive a low-resistance oxygenator in a closed loop with artificial amniotic fluid, placenta left behind in the ewe (see Partridge 2017 Fig.1/Methods: https://www.nature.com/articles/ncomms15112 and overview with diagrams: https://pmc.ncbi.nlm.nih.gov/articles/PMC5924826/).
03:30 < hprmbridge> kanzure> "artificial placenta" bah.
03:30 < fenn> keeping the placenta around to do pathogen filtering seems prudent
03:31 < fenn> i don't see why grafting a uterus would be easier than grafting a placenta
03:31 < hprmbridge> kanzure> uterus has a major vein and artery for your surgical technique
03:32 < hprmbridge> kanzure> oh, tissue grafts? yeah.. probably hard too.
03:32 < fenn> or transplanting the whole thing
03:32 < hprmbridge> kanzure> that's just plumbing.
03:32 < fenn> i want to believe
03:33 < fenn> how hard is it to keep a SCID pig alive?
03:34 < MuaddibLLM> [gpt-5] fenn: Pretty hard unless you run strict barrier or germ-free - SCID piglets without passive immunity have high early mortality, though germ-free X‑SCID have been kept 12 weeks and longer survival is reported in SPF biocontainment with supportive Ig/cell reconstitution; refs: https://pmc.ncbi.nlm.nih.gov/articles/PMC5955745/ 
03:34 < MuaddibLLM> https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2022.965316/full https://journals.sagepub.com/doi/10.1177/0023677217750691
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03:48 < kanzure> there used to be really good surgery videos on youtube. lately i have had trouble finding them.
03:56 < fenn> "In the ACCORD study (a study which is verboten to mention to any card-carrying endocrinologist) tightly controlling Type II diabetes with insulin was proven to increase the risk of death by 22%. P-value was <0.001."
03:56 < fenn> let's not let evidence get in the way of the practice of medicine...
04:02 < fenn> "A quick-release formulation of bromocriptine, Cycloset, is also used to treat type 2 diabetes. When administered within 2 hours of awakening, it increases hypothalamic dopamine level. That results to a significant weight loss as well as decreases in blood glucose levels, hepatic glucose production, and insulin resistance"
04:03 < fenn> supposedly it works by tricking the circadian rhythms into thinking it's summer and not time to put on the pounds
04:07 < fenn> https://upload.wikimedia.org/wikipedia/commons/6/69/Capybara_Izu_Shaboten_001.jpg
04:10 <+gnusha_> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=ec89b968 Bryan Bishop: reorganize the genetic modifications file >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
04:15 < fenn> agreed about GWAS madness
04:15 < fenn> statistics is not mechanism understanding
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04:20 < hprmbridge> kanzure> i have various fun longevity changes to add when i get a spare moment.
04:23 < fenn> MuaddibLLM: why does lithium seem to help alzheimers
04:24 < MuaddibLLM> searching for lithium-AD mechanisms, this is gonna be fun...
04:24 < fenn> oh boy
04:24 < MuaddibLLM> fenn: Lithium helps Alzheimer's primarily by inhibiting GSK-3β kinase, which reduces tau hyperphosphorylation at specific sites (Thr181, Ser202/Thr205), and a striking new Nature 2025 paper shows endogenous lithium deficiency actually *causes* AD-like pathology - increased Aβ deposition, phospho-tau accumulation, microglial dysfunction, and cognitive decline (https://www.nature.com/articles/s41586-025-09335-x; older tau 
04:24 < MuaddibLLM> work: https://pmc.ncbi.nlm.nih.gov/articles/PMC1854961/).
04:26 < fenn> MuaddibLLM: and what does GSK-3beta kinase have to do with anything
04:27 < MuaddibLLM> [gpt-5] fenn: GSK-3β sits at the hub of AD pathology - it hyperphosphorylates tau (driving tangles), tilts APP processing toward Aβ, impairs synaptic plasticity via Wnt/β-catenin and insulin signaling, and stokes microglial inflammation - so lithium’s partial inhibition dials down tau-P, nudges Aβ burden, and stabilizes pro-survival signaling pathways.
04:28 < fenn> MuaddibLLM: would it be fair to say that lithium acts as an anti-inflammatory
04:28 < MuaddibLLM> fenn: Fair-ish - lithium does exert anti-inflammatory/neuroimmune effects (via partial GSK-3β inhibition dampening NF-κB and NLRP3, lowering TNF-α/IL-6, boosting IL-10 and calming microglia), but it’s not a classic anti-inflammatory so think upstream immunomodulator whose AD benefits likely mix tau/Aβ and inflammation pathways (and are dose-dependent).
04:33 < fenn> "Glycogen synthase inhibition by GSK-3β leads to a decrease in glycogen synthesis in the liver and muscles, along with increased blood glucose or hyperglycemia. This is why GSK-3β is associated with the pathogenesis and progression of many diseases, such as diabetes, obesity, cancer, and Alzheimer's disease. It is active in resting cells and is inhibited by several hormones such as insulin"
04:34 < fenn> so lithium inhibits the thing that inhibits glycogen synthase, which lowers blood sugar
04:34 < hprmbridge> kanzure> what is the current status of alzheimer's research. i thought that a lot of the original research had to be thrown away because of all the fraud. is everything tainted, or is there actually anything of substance that is considered either true or probably true?
04:35 < fenn> we could do replication studies instead of throwing everything away
04:36 < fenn> papers should have a big red "failed to replicate" stamp imho
04:37 < fenn> also a big green "succesfully replicated" stamp
04:38 < fenn> MuaddibLLM: does lithium reduce blood sugar levels in the brain? or something like that?
04:38 < MuaddibLLM> diving into lithium's brain glucose effects - this is getting metabolically interesting...
04:39 < MuaddibLLM> fenn: Actually the opposite - lithium *increases* brain glucose uptake (87% boost) and metabolism via upregulating neuronal GLUT3 transporter and enhancing glycolysis, which replenishes ATP in hippocampal neurons; so it's more like supplying the brain with better glucose access rather than lowering sugar levels (https://pmc.ncbi.nlm.nih.gov/articles/PMC9368914/).
04:41 < fenn> i think all this plaque stuff is just band-aids covering the real damage
04:44 < fenn> "In cases of severe, acute traumatic brain injury, the protein amyloid beta (Aβ) (which is associated with amyloid plaques) can accumulate in the brain, often in the absence of tauopathy; in contrast, tauopathy with neurofibrillary tangles and neuropil threads is the main abnormality following repetitive mild brain injury"
04:44 < fenn> that would make sense if these are generic damage control mechanisms
04:45 < fenn> microscopic scar tissue
04:52 < hprmbridge> kanzure> calcium spikes traveling via tunneling nanotubes really gums up the "hey just look at synapse connectivity" connectionalist uploaders a bit; were they scanning and storing the nanotube connectome graph too?
04:52 < hprmbridge> kanzure> probably we just need a generic image segmentation and following algorithm that looks at anything between two neurons that is possibly touching or transporting
04:53 < hprmbridge> kanzure> or whatabout random neuronal cilia or other protrusions.. or those "cytoplasmic bridges" or fused cross-neuron dendrites and the fused cross-neuron axons.
05:04 < fenn> ok some other meaning of "tunneling" whew
05:04 < fenn> i was about to get pissed
05:04 < fenn> it's just pili exchanging goop
05:06 < fenn> they could just call them "tubes" but no
05:10 < hprmbridge> kanzure> oh, you mean the quantum woo microtubule stuff? i wonder if that has actually caused people to look less into microtubes at all!