--- Log opened Thu Jan 30 00:00:24 2020
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00:31 < nsh> .t 1222200483047182336
00:31 < EmmyNoether> My wife and I never talk to our kids. We ask them to submit all communications anonymously through rigorous and double-blind peer review. My daughter is 5 and has 21 publications in high-impact journals. My daughter can burn holes in furniture using only her eyes https://twitter.com/thebrometheus/status/1221034141765922816 (@mccormick_ted)
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12:14 < kanzure> delinquentme: welcome back...
12:15 < delinquentme> Howdy!
12:15 < delinquentme> Rapport really matters in communication, holy crap.
12:15 < delinquentme> Ok sooo yashgaroth nsh
12:15 < yashgaroth> mm
12:16 < delinquentme> Yesterday I presented this think to kanz about the cellular therapeutics.
12:16 < delinquentme> First off, do we semi-agree that Aubrey is onto something w his RepleniSENS request for research?
12:17 < delinquentme> That dwindling stem cell pools within a body are a hallmark of aging.
12:17 < delinquentme> Or well say: "At least a plausible contributor to the maladies of aging"
12:17 < yashgaroth> sure
12:18 < delinquentme> OK so then recuperating the stocks of multipotent stem cells withint the body could be of benefit.
12:18 < yashgaroth> in theory, yes
12:19 < delinquentme> Ok so then the problem associated with harvesting some of the latent stem cells + multiplying them is of course the erosion of telomeres ( im sure among other thigns )
12:20 < kanzure> harvesting differentiated cells and editing them is not a problem.
12:20 < delinquentme> ^^ correct
12:20 < delinquentme> but what edits is part of this discussion.
12:20 < yashgaroth> if you're modifying somatic cells, making sure they're unmutated and will adhere 100% to their reprogrammed lineage is another issue
12:21 < kanzure> no my contention with you was regarding the survivability of the edited cells when you inject them back in (and where are you injecting?)
12:21 < delinquentme> and also really important is: post manufacture / edits, is there benefit to having those cellular products invitro.  Im claiming "yes".
12:21 < delinquentme> primarily based off the exclusion of complexity related to delivery mechanisms.
12:21 < yashgaroth> beyond that, there is the issue of delivery, including making sure they get to their specific niches and contribute a useful percentage of cells to the organ
12:22 < kanzure> what i would want to see is a study in mice or rats where injected (GFP positive) stem cells are injected back into a host, and then we later see fluorescence throughout a whole organ or something
12:22 < yashgaroth> ^
12:22 < delinquentme> kanzure, unsure on survavability ( but extended telomeres is a hallmark of long-lived efficatious cells )
12:22 < kanzure> nah forget about longevity for a moment. just GFP and fluorescence.
12:23 < yashgaroth> more so thrivability than pure survivability, and it doesn't matter how long their telomeres are if they float around outside their niche and aren't coaxed into producing the correct cells
12:23 < delinquentme> Well right but we're also not sure that the "success" case for this is that the cells spread throught the entire organism
12:23 < yashgaroth> nah that'd be the success case
12:23 < delinquentme> perhaps just that the organ local to the injection is healthy.
12:24 < kanzure> for the local tissues they are responsible for.
12:24 < delinquentme> also how many generations does GFP hang around for?
12:24 < yashgaroth> as long as the cell is producing it
12:24 < kanzure> i mean genetic circuit for gfp. not just gfp protein swimming around in the stem cell.
12:24 < delinquentme> lol yeah. thats the question -- how long will that cell have the modified genetics to product GFP.
12:24 < yashgaroth> if it's tied to a housekeeping gene promoter, should be nearly indefinite if the cell is healthy
12:25 < kanzure> long enough... optogenetics experiments show neurons keep the optogenetic proteins for life, if it's in the genome it isn't going anywhere.
12:25 < kanzure> invoking optogenetics is overkill but whatever, i'm not a biologist
12:26 < delinquentme> "nd it doesn't matter how long their telomeres are if they float around outside their niche and aren't coaxed into producing the correct cells
12:26 < delinquentme> "
12:26 < kanzure> delinquentme: it's very possible that there's an existing study that does this. you can probably find it.
12:26 < delinquentme> Right bu this is one of the primary abstractions we'd hope to gain by manufacturing on existing, methylated ( "stateful" ) multipotent stem cells.
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12:28 < delinquentme> so yeah I think at some level I agree that the incorporated GFP would indicated that  the stem cell is effective.
12:28 < kanzure> i think the search term is either "stem cell replacement" or "stem cell transplantation" and GFP
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12:32 < yashgaroth> the question is also what proportion of 'exhausted' stem cells are in that state just because their telomeres are too short, whether that is the only bottleneck
12:33 < delinquentme> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791624/
12:33 < delinquentme> So yeah this is a "cut into the mouse locate a specific area of the heart, inject the modified stem cells. Wait 5 days. Retrieve hearts + examine "
12:34 < kanzure> this is a protocol, not an analysis
12:34 < delinquentme> "This is particularly important in evaluating stem cell survival and lineage differentiation into mature cardiovascular cells."
12:35 < delinquentme> Pics with the manufactured cells at least in the localized area.
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12:35 < yashgaroth> yes something using a protocol like that, but where they wait more than 5 days to check if the cells are replicating, integrating and generating tissue
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12:36 < yashgaroth> mix up some skin stem cells expressing telomerase and GFP, tattoo a mouse with them, and see if the tissue turns green (with and without inducing damage to the tissue to upregulate stem cell division and tissue turnover)
12:36 < kanzure> and other things like: is tissue composition purely a function of modified stem cell dosage? what percent of the tissue is now modified after n months?
12:37 < kanzure> 8% anti-aging mosaicism is probably useless.
12:37 < kanzure> chimerism?
12:37 < delinquentme> also consider what stem cells were used.  If these are progenitors to cardiac cells, we wouldnt necessarily see them in bones
12:38 < yashgaroth> yeah that's why skin is a good target, decently fast turnover and you don't need to sac the mouse to check how the cells are doing
12:38 < delinquentme> "8% anti-aging mosaicism is probably useless."  but is it distinguishable from control?  If yes, success.
12:39 < delinquentme> yashgaroth,  thats a clever protocol...
12:39 < delinquentme> though IDK if skin is the best candidate ( not hyper vascular )
12:40 < kanzure> what was church's stem cell purging method?
12:40 < delinquentme> Id think haemotopoetic cells would be good candidate
12:40 < delinquentme> https://en.wikipedia.org/wiki/Hematopoietic_stem_cell#/media/File:Hematopoiesis_simple.svg
12:40 < yashgaroth> it's not like you want the injected cells floating around in the bloostream, only immune cells regularly transit across the endothelium so stem cells would probably be stuck floating in yer blood rather than reaching their target tissue
12:41 < kanzure> also stem cell size vs capillary size.. something to consider.
12:41 < delinquentme> Oh... true yashgaroth.
12:41 < delinquentme> I was thining bc the varitety of differentiation lineage ( per pic above )
12:42 < yashgaroth> hematopoietic stem cell transplant happens all the time for leukemia, probably someone's done a study of how effective it is if you don't ablate the subject's bone marrow
12:42 < yashgaroth> but yes checking blood for gfp levels is also pretty easy
12:43 < delinquentme> "The long-term fate of mesenchymal stem cells labeled with magnetic resonance imaging-visible polymersomes in cerebral ischemia"
12:43 < delinquentme> https://www.dovepress.com/the-long-term-fate-of-mesenchymal-stem-cells-labeled-with-magnetic-res-peer-reviewed-fulltext-article-IJN
12:43 < yashgaroth> church's I think was the modified stem cells actively chemotaxing toward existing stem cells and then lysing them and taking over their niche like a parasite
12:44 < delinquentme> "Only a small fraction of grafted cells survived up to 8 weeks after transplantation. A minority of these surviving cells were differentiated into astrocytes, but not into neurons. "
12:44 < delinquentme> yashgaroth, thats a weird thought...  Like the body has some metric / understanding for the ideal stem-cell density?
12:45 < delinquentme> Like why would it chemotax to an existing stem cell?
12:45 < yashgaroth> you'd have to engineer it in
12:45 < delinquentme> ?
12:45 < delinquentme> I dont understand what you mean...
12:45 < yashgaroth> engineer a circuit into your injected cells that causes them to do it
12:46 < yashgaroth> it's still highly theoretical at the moment
12:47 < delinquentme> Oh nono I wasnt suggesting that we engineer that limit monitor, but instead that:
12:47 < kanzure> church's idea is to remove the existing stem cells because you want to replace them with your modified cells. so the modified cells can attack the pre-existing stem cells.
12:47 < delinquentme> "If the implanted stem cell seeked out the existing one" why would it?
12:48 < delinquentme> But why would the new cells attack the old stem cells?
12:48 < yashgaroth> because we tell them to, with genetics
12:48 < delinquentme> wait that was an ENGINEERED behavior>???
12:48 < yashgaroth> and instead of the old, unmodified stem cell producing tissue for that organ, your replacement cell would
12:48 < yashgaroth> oh god yes
12:49 < kanzure> it's a concept not actively working.
12:49 < delinquentme> .... wait. thats been done?
12:49 < kanzure> no.
12:49 < delinquentme> OHHhh ok ok ok.
12:49 < kanzure> 12:46 < yashgaroth> it's still highly theoretical at the moment
12:49 < delinquentme> kanzure, predicated upon presumption i can read. wtf.
12:50 < delinquentme> But in my, likley incorrect thinking, why replace them when if the stores of funcitonal cells are sufficient, just wait for shit cells to senesce?
12:51 < yashgaroth> that's actually another issue, even if you have a small fraction of modified cells producing 'good' tissue, the existing senescent cells might inhibit them anyway...though there are other methods of dealing with that
12:52 < yashgaroth> if those 'shit cells' are neural or cardiac tissue, it's not easy to wait for them to just die off
12:53 < yashgaroth> the question is also whether the old stem cells are producing fewer cells, or just bad cells (or both)
12:55 < delinquentme> re: existing inhibition...  an coarse solution might be more "good stem cells"
12:55 < delinquentme> But yeah the damage that the bad stem cells are causing is another discussion, more in the wheelhouse of other therapies.
12:56 < delinquentme> Ok so we need a study basically outlining some time of modified multipotent stem cell creating healthy progeny which has integrated into the organism.
12:59 < yashgaroth> yeah do the mouse skin thing for a start, hell you could sell a skin therapy outside of the anti-aging community since a lot of people subscribe to the "better to look good than to feel good" philosophy
13:00 < yashgaroth> and a lot more people are okay with cell tattoos than getting every internal organ injected repeatedly
13:01 < delinquentme> "The study showed that the transplanted neural stem cells had indeed matured into nerve cells that not only integrated into the brain’s circuitry at the transplantation site but could be induced to fire electrical signals on command, and that this signaling triggered activity in other areas of the brain."
13:01 < delinquentme> "she and her colleagues combined functional magnetic resonance imaging, or fMRI, with a relatively new but increasingly widespread technology known as optogenetics..."
13:01 < delinquentme> "let the scientists selectively stimulate only nerve cells derived from newly transplanted neural stem cells, while simultaneously assessing resulting nerve-cell activity at the site of the transplant and elsewhere in the brain. "
13:01 < delinquentme> https://med.stanford.edu/news/all-news/2015/04/scientists-find-way-to-monitor-progress-of-stem-cells.html
13:03 < yashgaroth> ah fMRI, the GWAS of the neuro world
13:03 < delinquentme> Above research is using skin cells as the input cell-stock, giving those cells iPSC manufacuring prior to therapy.
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13:05 < yashgaroth> I would be extremely cautious about transdifferentiating cells like that for human therapy, a skin cells's neural promoters (and vice versa) are gonna be heavily degraded by decades of CpG methylation/mutation
13:06 < yashgaroth> and iPSCs in general, it's fine in mice when they only live a couple years and rarely get cancer, different for humans if they'll be living for decades after treatment
13:07 < delinquentme> yashgaroth, wholly agree, although with less resolved reasoning.  Hence my suggestion of sucking the existing ones out + extending their lifespans
13:09 < yashgaroth> yeah it's not just the lifespan/telomere length though, it's accumulated mutations; and if you're not dedifferentiating them before you grow them it's a massive pain since keeping primary cells alive in a dish is a pain, moreso with stem cells, and even moreso if you're trying to get a large number of them
13:11 < yashgaroth> and even more moreso if you have to grow a specific person's cells in each case, rather than mice which are basically all already clones of each other due to inbreeding
13:18 < delinquentme> I think its safe to assume that fully differentiated cells have fewer possible ways they could harm an organism as compared to multipotent cells... right?
13:19 < delinquentme> primary cell == somatic cell?
13:20 < delinquentme> wait regarding immuno compatibility ... isnt this determined by relatively few genes where they end up expressing some kind of surface receptor proteins?
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13:27 < delinquentme> https://www.futuremedicine.com/doi/10.2217/rme-2018-0161
13:32 < yashgaroth> yeah if they're correctly differentiated they're safer than multipotent cells; primary cells are any removed from an organism and then grown in a dish, they don't have to be somatic
13:32 < yashgaroth> and if you can develop a universal cell that can be transplanted into any person without immune rejection, that'd be worth multiple nobels
13:33 < delinquentme> Wtffffff. They expanded the above cells in FBS then reinjected them.
13:33 < delinquentme> So the FDA has a term they use of "manufacturing" which that, id assume, falls under -- and is something they're interested in having their fingers in.
13:33 < yashgaroth> well there was other media in there too, but yeah that's pretty standard
13:35 < delinquentme> it makes me wonder how much of a precedent there is for expansion of cell lines in FBS...
13:35 < delinquentme> disgusting IMHO, but if the AUS equivalent of the FDA allows it, i guess ill take it?
13:36 < yashgaroth> aside from potential exposure to prions, FBS is hardly the most disgusting reagent in the lab
13:37 < delinquentme> Oh I agree, 'in the lab', but this is injected into people...
13:37 < delinquentme> Does something more disgusting, which was safe for therapeutic use, come to mind yashgaroth ?
13:38 < yashgaroth> well they'd wash the FBS off the cells before injection, but there's plenty of nasty shit in vaccines
13:38 < yashgaroth> there are synthetic FBS alternatives, but for cells as finicky as primary stem cells it's a worthwhile tradeoff since nothing works quite as well as baby cow blood
13:42 < delinquentme> Yeah idk yashgaroth.  If we ever work together I think id prefer a lower return on cell pool growth , w the tradeoff of simplifiying a host of variables w the cow juice
13:42 < delinquentme> https://www.ncbi.nlm.nih.gov/pubmed/23133515
13:42 < delinquentme> "Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials."
13:44 < delinquentme> "Based on the current clinical trials, MSC therapy appears safe. However, further larger scale controlled clinical trials with rigorous reporting of adverse events are required to further define the safety profile of MSCs."
13:44 < delinquentme> And this is of course the very therapy that hollywood talks about.
13:45 < delinquentme> But I do like the skin as the testbed -- it being superficial feels really helpful.
13:48 < yashgaroth> yeah it's pretty ideal, and in research you want to simplify as much as possible, rather than trying to answer a dozen different questions at once
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15:38 < kanzure> yahoo groups archiving status https://data-horde.blogspot.com/2020/01/saving-private-groups-this-time-mission.html
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20:08 < lsneff> .wik tulpa
20:08 < EmmyNoether> "Tulpa is a concept in mysticism and the paranormal of a being or object which is created through spiritual or mental powers. It was adapted by 20th century theosophists from Tibetan sprul-pa (Tibetan: .mw-parser-output .uchen{font-family:Jomolhari,'Noto Sans [...]" - https://en.wikipedia.org/wiki/Tulpa
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20:29 < lsneff> Some people claim to be able to host secondary (and sometimes more) fully autonomous sentient beings in their mind (tulpas)
20:29 < lsneff> Interesting, no?
20:30 < lsneff> The two hemispheres already have weird stuff going on, more wouldn't surprise me
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21:21 < kanzure> what
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21:55  * fenn constructs a mechanical eye-rolling machine
21:56 < fenn> specifications. discards over 9000 ideas a minute
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--- Log closed Fri Jan 31 00:00:24 2020