--- Log opened Mon Sep 15 00:00:40 2025
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00:48 < hprmbridge> kanzure> "A principal odor map unifies diverse tasks in olfactory perception" https://www.science.org/doi/10.1126/science.ade4401 odor prediction (2023)
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00:55 < fenn> somehow i've read this paper before
00:55 < hprmbridge> kanzure> olfactory section of genetic-modifications.mdwn is lacking.
01:03 < hprmbridge> kanzure> "Kv1.3−/− mice have a 1,000- to 10,000-fold lower threshold for detection of odors and an increased ability to discriminate between odorants" https://pmc.ncbi.nlm.nih.gov/articles/PMC2737549/
01:04 < fenn> i'm not sure i'd want to curse my children with this
01:09 < hprmbridge> kanzure> my plan: "develop a recombinase-driven genetic circuit that enables olfactory sensory neurons to stochastically assemble novel olfactory receptor variants from modular gene segment, analogous to immune V(D)J recombination. make a biologically plausible strategy to generate in vivo receptor diversity and systematically enhancing odor sensitivity and selectivity."
01:11 < hprmbridge> kanzure> wait, why can't we smell viruses?
01:14 < fenn> they're anti-inductive
01:15 < hprmbridge> kanzure> we have people perceiving various cancers but viruses are off limits?
01:15 < fenn> if you had a reason to smell them, i.e. you are a viable host, then they would have evolved to not be recognizable by the receptor you used to smell them
01:15 < hprmbridge> kanzure> immune systems devastated!
01:15 < fenn> they're probably not smelling the cancer itself but rather the immune response
01:16 < fenn> and you *can* smell sick people
01:18 < hprmbridge> kanzure> haha the LLMs are so mad at me "Most viruses/antigens aren’t smells. They’re particles or proteins."
01:20 < fenn> i mean they are a lot bigger
01:21 < hprmbridge> kanzure> antibodies can do shape subset matching.
01:21 < fenn> a lot of the things we smell are actually reaction products catalyzed by the material, or bacteria that live on it, or something like that
01:22 < hprmbridge> kanzure> anyway, we don't need to be stuck with the genomically encoded olfactory receptors. we can have background level of recombination creating new receptors with new detection throughout life.
01:22 < fenn> size controls how quickly molecules can diffuse through mucus, and i guess the mucus is designed so that viruses can't attach to the cells secreting the mucus
01:23 < hprmbridge> kanzure> "you smell like HIV" looool
01:23 < hprmbridge> kanzure> "got that herpes simplex smell"
01:24 < fenn> it would be better to have a separate smell organ that isn't hooked directly into all this low level stuff (ask me how i know)
01:24 < fenn> just another sense channel for the cortex
01:26 < fenn> the majority of modern humans have really saturated dulled noses from all the chemicals, and probably a lack of folate
01:27 < fenn> it used to be expensive to get strong perfumes and somehow nobody updated
01:39 < hprmbridge> kanzure> "AAV-mediated neuronal expression of an scFv antibody" https://pmc.ncbi.nlm.nih.gov/articles/PMC9931599/ mainly to catch stuff in a synapse
01:40 < hprmbridge> kanzure> "programmable antigen-gated G-protein-coupled engineered receptors (PAGERs)" https://www.nature.com/articles/s41586-024-08282-3
01:43 < hprmbridge> kanzure> general review about controlling ion channel function with antibodies https://pmc.ncbi.nlm.nih.gov/articles/PMC9058206/
01:57 < hprmbridge> kanzure> oh, you could combine that DREADD antigen gated GPCR thing with the intracellular memory recording devices like the protein one. or even as an intracellular sensor.
02:14 < hprmbridge> kanzure> "In insects, olfactory receptors are members of an unrelated group of ligand-gated ion channels." and not GPRCs.
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06:58 < kanzure> there seems to be some evidence of programmable self-programming other than CRISPR and VD(J) recombination:
06:58 < kanzure> diversity-generating retroelements (DGRs) like by bordatella phage tail fiber to reprogram host-receptor binding, where reverse transcriptase casettes copy a "template repeat" into a "variable repeat" with mutagenesis, creating "hypervariable protein loops" on a target, like receptor-binding domains.
06:59 < kanzure> shufflons: site-specific recombinase card shuffles, like where a recombinase (Rci) inverts multiple DNA cassettes to recombine the C-terminus of an adhesin, yielding many tip variants. example: PilV pilus tip targeting.
07:01 < kanzure> various expression-modulating schemes across a variety of surface filaments.. not as interesting but this can obviously create a form of selectivity for surface binding preference.
07:02 < kanzure> lotta pilus sequence recombination schemes in bacteria... "segmental gene conversion from silent cassettes, generating enormous surface diversity".. or "antigenic variation" schemes.
07:02 < kanzure> and adhesins, not just pilus resequencing.
07:04 < kanzure> "Synthetic shufflon-like recombination systems" https://www.biorxiv.org/content/10.1101/2024.10.25.620183v2
07:05 < kanzure> "Synthetic diversity generating retroelements for in vivo targeted hyper-mutagenesis" https://www.biorxiv.org/content/10.1101/2025.03.24.644984v1 "DGRs coupled to recombineering (DGRec)"
07:10 < kanzure> other schemes for in vivo self-recombineering or auto-evolution: CRISPR-X (https://pubmed.ncbi.nlm.nih.gov/27798611/), TRACE / T7-RNAP-guided mutagenesis (https://www.nature.com/articles/s41467-021-21876-z), CoMuTER (Type I-E Cas3 mutagenesis) (https://www.nature.com/articles/s41467-023-39087-z), base editor and prime editor randomization toolkits ...
07:10 < kanzure> ...(https://pmc.ncbi.nlm.nih.gov/articles/PMC10828429/).
07:15 < kanzure> there are various vivo continuous evolution/mutagenesis schemes... but not sure if they require in vitro steps before utilization. also some of them are virus-based schemes, which may not be ideal in vivo inside animal.
07:32 < kanzure> has anyone repurposed B cell in vivo affinity maturation for the purposes of the recombination and selection of non-antibody related targets, like ligands, receptors, or other proteins?
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07:38 < kanzure> yes:
07:39 < kanzure> "Virus-free continuous directed evolution in human cells using somatic hypermutation" https://www.biorxiv.org/content/10.1101/2024.12.24.629435v1 (2024)
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08:03 <+gnusha_> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=9b8ae510 Bryan Bishop: olfactory enhancements >> http://diyhpl.us/diyhpluswiki/organoids/
08:12 < kanzure> self-organizing decentralized p2p networks using freenet/sandberg's virtual address sample-and-swap technique https://diyhpl.us/~bryan/papers2/security/The%20RedKing%20Hivemind%20-%202022.pdf
10:18 < kanzure> that protein recording system (cytotape) got me thinking.. what about using cellular cilium or other cellular hair-like extrusions to record information from inside the cell? with fluorescent markers you might be able to read out the time logged information via microscopy.
10:19 < kanzure> alternatively, you could use lineage tracing style techniques in the human hair bulb or hair matrix to encode information into keratinocytes or keratin filaments inside of keratinocytes.
10:21 < kanzure> or use the protein tunneling nanotubes (TNTs) for this purpose by incorporating other proteins into the filament structure, by binding into the wall or structure of the TNT instead of having cargo tunnel through it.
10:23 < kanzure> "TNTs can propagate evoked Ca2+ signals, as imaged with fluorescent Ca2+ indicators" jeeze we're so screwed.
10:30 < kanzure> maybe we can make a system to record information from neurons this way, producing a long extrusion protein filament that then gets excised and then moved into the bloodstream. later, collect the filaments and sequence or optically interrogate them.
10:43 <+gnusha_> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=e4df4f70 Bryan Bishop: hair follicles and cell surface-bound protein filaments as information recorders for debugging >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
10:44 < kanzure> "In cancer biology, microtentacles are extremely thin, actin-rich membrane projections that form on the surface of detached or circulating cancer cells. These are not classical filopedia or invadopedia; instead, microtentacles are tubulin-based structures enriched in detyrosinated α-tubulin and EB1. Microtentacles extend for tens of micrometers from the cell body and persist for hours or ...
10:44 < kanzure> ...days."
11:10 < kanzure> vesicle incorporation and release of protein tapes would be more immune friendly :\
11:18 < kanzure> synthetic horizontal gene transfer (like via perforin-granzyme pathway) should be able to create stealthy gene editing in vivo, as long as at least one bacteria cell survives long enough to reprogram at least one autologous cell to participate in the horizontal scheme.
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12:44 < kanzure> "Biomimetic sniffing device increases odorant detection by a factor of up to 18" https://pmc.ncbi.nlm.nih.gov/articles/PMC5131614/ someone should make a breathing-synchronized air injection mask, with sample humidification, to amplify sniff-delivered odor flux to the human (or canine) olfactory slit.
12:49 < kanzure> "smell-aids" https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-03999-y "We attempt to invent “Smell-Aids” by non-invasively enhancing intranasal odorant delivery to the olfactory epithelium, using two prototypes: (a) a nasal foam plug with a diagonal channel embedded to direct air/odor flow upwards to the olfactory region; (b) a clip (similar to what synchronized swimmers ...
12:49 < kanzure> ...use) pinching a critical nasal valve region that may intensify the nasal airflow vortex to the olfactory region."
12:49 < kanzure> https://www.rayallen.com/k9-power-wake-scent-cone-training-system/
12:51 < kanzure> what...
12:51 < kanzure> it's just a fan to blow some smelly stuff at the dogs (not a mask)
13:07 < hprmbridge> kanzure> "Rich Pell recently became the first person to “illuminate and photograph a living microbe under a microscope” using “light from a star outside of the Earth’s solar system.” Right now, he is trying to become the first person to grow an organism on Earth using solely the light from a different sun.  It’s an art project, called Stellar Harvest. The gist is that Pell is going to take some diatoms and
13:07 < hprmbridge> kanzure> slowly "evolve" them until they can live on less and less sunlight. Diatoms can already live in low-light places, including deep ocean waters, but the Sun is ~13 billion times brighter than the next brightest star seen from Earth. So these diatoms will need to adapt to live on even fewer photons."
13:07 < hprmbridge> kanzure> "Also, his museum in Pittsburgh has a goat that was engineered to produce spider silk in its milk (taxidermy). His entire museum, in fact, is devoted to those “organisms that have been intentionally altered by humans through domestication, breeding, or engineering.”"
13:08 < hprmbridge> kanzure> https://www.postnatural.org/
13:12 < hprmbridge> kanzure> cremieux says "I've decided I will subject myself to a gene therapy to make my body produce antibodies that block the activin type II receptor. In effect, I will be endogenously producing Eli Lilly's drug bimagrumab [for muscle mass]." link unrelated, https://www.cremieux.xyz/p/ozempic-and-muscle-mass
13:20 < hprmbridge> kanzure> something about analogs of 11-cis-retinal with altered color response profiles for altered vision https://x.com/louisvarge/status/1967410501194780783
13:55 < hprmbridge> Eli> they need a new name for this drug. Chadumab or something like that.
14:02 < fenn> cremieux's "this is a timed post" written in one hour is probably the biggest humblebrag i've ever seen
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15:14 <+gnusha_> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=2c949bc2 Bryan Bishop: add downloadable immunity scheme, and an anti-viral scheme >> 
15:14 <+gnusha_> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=f14bf9d7 Bryan Bishop: hearing range enhancement notes >> http://diyhpl.us/diyhpluswiki/organoids/
15:18 < fenn> re dental caries vaccine, "Wives and children of the two subjects infected with the mutacin up-producing S. mutans strain were not colonized when tested 14 years after the initial infection regimen"
15:19 < fenn> so you gotta get the procedure done
15:19 < fenn> this was with BCS3-L1
15:21 < fenn> jeffrey hillman worked tirelessly on the caries vaccine for 20 years and nothing came of it
15:22 < L29Ah> what procedure?
15:23 < L29Ah> i could use a caries vaccine, caries is surprisingly expensive to handle!
15:23 < fenn> deep teeth cleaning and application of a dose of BCS3-L1
15:24 < fenn> "polish the teeth with dental pumice" may not be necessary but i don't know how this relates to dosing
15:24 < L29Ah> will it allow me to cut my brushing to twice a week?
15:24 < fenn> i was hoping it would just spread through the population as a live vaccine
15:25 < fenn> https://luminaprobiotic.com/products/lumina-probiotic-cosmetic-toothpaste via https://www.cremieux.xyz/p/the-rise-and-impending-fall-of-the
15:25 < fenn> i think it will allow you to cut your brushing to zero, but it's probably still a good idea
15:26 < fenn> to reduce inflammation
15:27 < fenn> "because of the parent-to-child transmission described at this article’s outset, if a would-be parent is colonized, their kids will end up living a life that’s likely to include far fewer or zero caries."
15:29 < kanzure> i thought cremieux meant that he would take an antibody for the receptor, not that he's doing an mRNA gene therapy :( suddenly much less interesting.
15:29 < fenn> it should be easy to culture and verify since it generates an antibiotic, so it would clear a zone around the colony
15:29 < fenn> because mRNA is not permanent? why is it less interesting?
15:29 < kanzure> dosage and expression issues
15:29 < fenn> why would taking an antibody be interesting?
15:30 < kanzure> bimagrumab causes significant muscle mass development
15:30 < kanzure> because it is an antibody antagonist of uhh i think activin type II receptor
15:31 < fenn> let me rephrase. why would taking an antibody be more interesting than mRNA?
15:31 < kanzure> because it will actually work to cause muscle growth
15:31 < MuaddibLLM> [gpt-5] Because a dosed antibody gives predictable, titratable PK/PD and receptor occupancy with clean reversibility (weeks-long half-life, no transfection step), whereas mRNA adds delivery/tropism and expression-kinetic uncertainty (bursty translation, immunogenicity, hard-to-target muscle) that can overshoot a tight window like ActRII signaling.
15:31 < L29Ah> i wonder how hard would it be to culture the lumina to give it to everyone in our community, $250 bites but is still a good offer if it really delivers cavities' elimination
15:32 < L29Ah> MuaddibLLM: what do you think?
15:32 < kanzure> his approach is intravenous plasmid injection
15:32 < fenn> one dentist visit is $250
15:32 < MuaddibLLM> Error: No valid text or tool use found in response
15:32 < L29Ah> my last dentist visit was 30e
15:32 < L29Ah> pasky: :(
15:32 < fenn> congrats :|
15:32 <+gnusha_> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=8049cac0 Bryan Bishop: reorganize some of the muscle genetics for endurance vs strength >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
15:33 < L29Ah> fenn: my 2024 income was 1913e
15:33 < fenn> what is the story of this company Lumina? how did they get the strain? what's their ideology?
15:34 < fenn> er, lantern bioworks
15:34 < pasky> yeah sorry !u be like that sometimes, will fix today/tomorrow
15:34 < pasky> it returns just <thinking> block
15:34 < kanzure> fenn: isn't this the SIAI/MIRI offshoot?
15:42 < L29Ah> MuaddibLLM: !h
15:42 < MuaddibLLM> default is serious agentic mode with web tools (['openai:gpt-5', 'anthropic:claude-sonnet-4-20250514']), !d is explicit sarcastic diss mode (anthropic:claude-sonnet-4-20250514), !u is unsafe mode (openrouter:moonshotai/kimi-k2#fireworks,together,groq), !a forces thinking, !p is Perplexity (prefer English!)
15:43 < L29Ah> MuaddibLLM: !a what do you think on the culturing?
15:43 < MuaddibLLM> [gpt-5] L29Ah: I’d strongly avoid DIY-culturing and seeding a community with an engineered oral strain - without validated ID, tox and resistance panels, HGT risk, GMP-grade production, and consent oversight you’re courting dysbiosis and liability; stick to proven low-risk caries controls for now (fluoride, xylitol, varnish, S. salivarius K12/M18) until a regulated prep exists.
15:43 < fenn> the other reason to culture is to verify tooth colonization by the vaccine strain
15:45 < fenn> BCS3-L1's horizontal gene transfer machinery was disabled, to prevent it from sharing the antibiotic producing genes
15:46 < fenn> it may still be possible but less likely
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16:16 < hprmbridge> kanzure> from the ancient backlogs: https://cdn.discordapp.com/attachments/1064664282450628710/1417288032331104368/image0.jpg?ex=68c9efd6&is=68c89e56&hm=1b88f2a2a64432f08cddc7c79f96aa73904cdad541170510bf766bfc417e8263&
16:55 < L29Ah> needs more jpeg
16:56 < fenn> some boring history of lantern bioworks https://twitter.com/yishan/status/1780131552615420189
17:00 < fenn> "But the FDA required them to find a cohort of 300 healthy 18-30 year olds who lived alone, not near a school zone, and had fully removable teeth. Let me repeat that: they wanted Oragenics to find 300 young people with dentures."
17:01 < fenn> "the FDA process these days is so onerous and cumbersome and sufficiently removed from the questions of safety and efficacy that they are considered something that makes a company uninvestable to many." yeesh
17:02 < hprmbridge> kanzure> pop quiz, how many clinical trials are currently in progress right now?
17:02 < L29Ah> over a thousand
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18:59 < hprmbridge> kanzure> germline longevity section is underdeveloped :/
19:14 < L29Ah> it is unlikely to take off without funding high quality humans en masse or achieving longevity escape velocity for at least some of the living people
19:15 < L29Ah> since the beneficiaries don't exist
19:15 < hprmbridge> kanzure> there's lots of stuff in the literature for germline genome longevity mods.
20:24 < hprmbridge> kanzure> "TSMC branded honey" hmm.
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--- Log closed Tue Sep 16 00:00:41 2025