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Autoimmune Replacement Therapy

Replace the bone marrow
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The immune system doesn't set itself up & calibrate itself to recognize what's good & what's not until fairly well along in fetal development, we know this.

And most of the immune system (antibodies & whatnot) is in the blood, we know this too.

So..

Step one, we take a small sample of cells from patient A & introduce these to a pig fetus, let them get to know each other & shake hands, your baby piglet when it's born now has an immune system that recognizes patient A's cells as what's good as well as it's own.

Step two, allow your piglet to grow to a suitable size then harvest it's bone marrow (put this & the rest of the pig on ice, you'll need it later).

Step three, remove patient A's bone marrow & replace with the pigs, you may need to keep him on a few support machines while things sort themselves out.

Step four, patient A now has an immune system that recognizes both patient A's own cells & the pigs as what's good..

You can now go ahead & transplant any organs from the pig (you need to go get it out of the fridge first of course) into patient A without any fear of rejection.

If patient A has gone for the deluxe package there'll be some happy little piglet clones running around on a nice farm somewhere, eagerly awaiting his unexpected need for a new pancreas, lungs or sundry other organs.

Of course I may have got something horribly wrong here.

Skewed, Dec 11 2018

My thinking has progressed a bit. Early_20foetal_20hu...lant_20inoculations
I'm not saying the new direction is good, just a little bit different. [Skewed, Dec 11 2018]

Same Idea https://biology.sta...tion-of-trans-speci
Biology Stack Exchange [Skewed, Dec 24 2018]

NCBI June 2011 Immuno-intervention.. https://www.ncbi.nl...rticles/PMC3178004/
"Extensive studies of organ and tissue tolerance induction via bone marrow transplantation were carried out early in the development of the miniature swine model" [Skewed, Dec 31 2018]

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       <Starts collecting sticks and kindling for when [bs0] arrives and orders the roasting to commence/>
8th of 7, Dec 11 2018
  

       This seems like quite a drastic solution to a problem - all this business about removing bone marrow.   

       All you need do is to ensure that (a) the human is tolerant of pig antigens and (b) any pig tissues transplanted into the human do not include pig immune cells which would attack the normal human antigens.   

       For (a), you just need to make a piglet smoothie and inject it into the human foetus. Of course, you'd want to be pretty sure your pig wasn't carrying any pathogens that can infect humans, since the human would then tolerate such pathogens instead of raising an immune response to them. You'd probably also want to ensure that the pig smoothie didn't contain any viable cells.   

       For (b), well, I guess the danger would that pig immune cells of one type or another, lurking in the transplanted piggy tissues, might survive and replicate in the human and attack normal human antigens. But it's not hard to make pigs with no immune system. So that's the easy way to solve (b).
MaxwellBuchanan, Dec 11 2018
  

       Yes that was my original idea & I still think it's a good one (they're letting me have pointed crayons again next week), but it's not much use for any of us that aren't still fetuses.
Skewed, Dec 11 2018
  

       Ah, right, I see your point. Well, it's probably easier (and I think being tried) to just tinker with a pig* until it's sufficiently human not to provoke an immune response in humans. Your tinkered pig would probably have no immune system, since immune-related genes are major contributors to immunogenicity (for instance, in human-human transplants).   

       *Tinkering with pigs is still legal in the Irish Republic; it's one of the less-discussed problems with Brexit.
MaxwellBuchanan, Dec 11 2018
  

       Then again, if you've got money to spare, just get yourself cloned - there's no real reason why it can't be done. Make sure the resulting child is anencephalic, and you're good to go.
MaxwellBuchanan, Dec 11 2018
  

       // Make sure the resulting child is anencephalic //   

       So what you're implying is that somewhere, the original of Justin Bieber is living quietly until one of his organs fails ?   

       There's a flaw in the "clone yourself" idea, though. If the disease you're planning to protect yourself against has a significant genetic component, won't that fault be perpetuated in the clone ? Then you'd be replacing one failed part with an identical (if slightly newer) one that's equally prone to the same inevitable failure mode, just like owning an apple product.   

       What you really need is a Version 1.1, with the majority of the significant bugs fixed.   

       // they're letting me have pointed crayons again next week //   

       <envy/>
8th of 7, Dec 11 2018
  

       //<Starts collecting sticks and kindling for when [bs0] arrives and orders the roasting to commence//   

       So very kind, it's bloody freezing here.   

       If I get this idea, then you're making a human tolerant pig immune system, swapping that into a human so at some future point you can freely swap in spare organs. There's a catch or two.   

       //Step three, remove patient A's bone marrow//   

       You can't really remove bone marrow, well you can a bit, like with a bone marrow donor, but you can't get much of it. Definitely not all. Normally, bone marrow recipients have no viable bone marrow left following particularly brutal chemotherapy or whole body irradiation. This is also the protocol if you want to replace the bone marrow experimentally in a mouse for example. You irradiate the mouse, and then transplant in bone marrow from another mouse, say a GFP-mouse that you can then use for tracking experiments. So yeah, you can't really remove it.   

       //Step four, patient A now has an immune system that recognizes both patient A's own cells & the pigs as what's good..//   

       Except the pig is dead. You did mention clones, so that might not be a problem. Except the clone will likely be dead too, mainly because they only live ~7 years. That highlights another problem, your pig immune system and bone marrow are going to age badly, it's off by about 10 fold.   

       I think the prevailing wisdom* is to try and remove or humanize antigens on pig organs. It's likely to be more complicated than that though, cells are always fusing and swapping stuff. Organs are signaling with molecules that interact with the immune system, maybe in different ways. Then there's all this innate immunity stuff which operates down to the organelle level. Immunology is far from being well understood.   

       *not always the best choice, guardians of prevailing wisdom are often close to retirement and therefore not that invested.
bs0u0155, Dec 11 2018
  

       //can't really remove bone marrow//   

       Don't they normally kill it off with chemotherapy before a bone marrow transplant? ah yes, you said, so do that then.   

       //your pig immune system and bone marrow are going to age badly, it's off by about 10 fold.//   

       That seems to mean humanized pig organs would suffer the same fate, or is bone marrow a special case?   

       If pig cells aging faster really is a problem then just humanize the bone marrow the same as you would any other organ, then the human cells in the "organ" (bone marrow in this instance) will reproduce to fill in the blanks as the pig cells age & die.   

       //Except the pig is dead.//   

       Yes, we did say to put it in the fridge.   

       //they only live ~7 years//   

       Divide the original embryo while it's still in the blastocyst stage (or is that done before?) & keep a handful of the resulting spare embryos on ice, use them for in vitro fertilization when your client needs some organs, won't take long, keep him hooked to appropriate machines while he waits.   

       Or just start new clones every three years or so, then there's always an adult available for harvesting.
Skewed, Dec 11 2018
  

       //they only live ~7 years//   

       So, what we really ought to focus on is a wide-ranging research program centred around elephants. Once they're established as a model organism and organ donor on a large scale, the entire endangered-species problem will simply go away. Moreover, ivory could be harvested, and would help fund the research. Of course, labs will need a bit of a redesign, and some sort of custom fork-lift will be needed to get the nozzles of the water bottles through the wire cage front, but these aren't the sort of problems to discourage one unduly. We probably also ought to get [8th] developing a suitable guillotine, perhaps just by scaling up the existing rat-and-mouse dispatchers.
MaxwellBuchanan, Dec 11 2018
  

       //we really ought to focus on is a wide-ranging research program centred around elephants//   

       I've told you before, I'm not doing a penis transplant with an elephants shlong (for a start I'm not licensed), so stop angling for it, you'll just have make do with what you've got.   

       <reads on/>   

       //labs will need a bit of a redesign, and some sort of custom fork-lift will be needed to get the nozzles of the water bottles through the wire//   

       <nearly chokes to death laughing with a mouthful of food/>
Skewed, Dec 11 2018
  

       //Don't they normally kill it off with chemotherapy before a bone marrow transplant? //   

       They're normally trying to kill an aggressive blood-borne cancer. Often they push so hard the bone marrow is damaged, OR the bone marrow is considered a potential store so they finish it off on purpose. It's not fun though.   

       //pig cells aging faster really is a problem then just humanize the bone marrow//   

       What is doable, is growing bone marrow. It's nice and stem-y, probably represents a good candidate for editing. I wonder if a bone marrow top up in your 80's would perk you up a bit?   

       The easy way to do that is to get a transplant from the human. You then need to solve the problem of rejection. I think we're just slowly making an expensive pig here.   

       // So, what we really ought to focus on is a wide- ranging research program centred around elephants.//   

       I've been saying something similar for years. It's infuriating to get a wonderful antibody only to have the whole supply dry up because it was from one mouse/rat. So scale up. Elephant primary followed by blue-whale anti-elephant. We're going to need a much bigger centrifuge.
bs0u0155, Dec 11 2018
  

       //You then need to solve the problem of rejection//   

       But I thought I had?   

       Step one, we take a small sample of cells from patient A & donor B & introduce these to a pig fetus..   

       Step two & three, as above.   

       Step four, patient A now has an immune system that recognizes both donor B's cells & patient A's cells (as well as the pigs) as it's own.   

       Presto! no rejection.
Skewed, Dec 11 2018
  

       // some sort of custom fork-lift will be needed to get the nozzles of the water bottles through the wire cage front //   

       What about an overhead crane ?   

       // but these aren't the sort of problems to discourage one unduly. //   

       Ever the optimist. You're overdoing the little green tablets again.   

       // ought to get [8th] developing a suitable guillotine //   

       Oh great, yeah, why not just hand over the most challenging aspect of the project on a fixed-price contract and then whine constantly when delivery's a bit late, or there are unforeseen problems because of your badly-specified User Requirement ...   

       And we haven't been paid for the last job, yet. Or the one before. In fact, you never pay. And that wretched brother of yours lost our okapi-stretcher in a bet ... that was an antique, irreplaceable... and the harpsichord keyboard is stained with something, no idea what but it won't come out, and they're ivory, again irreplaceable... and the Rentishams preference shares still haven't paid a dividend...   

       // We're going to need a much bigger centrifuge. //   

       For separating the elephants from the anomalously-large great white sharks ?   

       //Except the pig is dead.//   

       Not until you open the box. Until then, it's in an indeterminate quantum state.   

       // So very kind, it's bloody freezing here. //   

       No problem, any unused stuff will go on the Buchanan family solstice bonfire.
8th of 7, Dec 11 2018
  

       //I've told you before, I'm not doing a penis transplant with an elephants shlong (for a start I'm not licensed), so stop angling for it, you'll just have make do with what you've got.// That's easy for you to say - you don't have to live with it. If surgery can't give me something smaller I've no idea what I'll do.   

       //Rentishams preference shares still haven't paid a dividend// You really never read the small print, do you, [8th]? When we said "an annual dividend of 8-12% seems a reasonable forecast", we also asked that you pay it on the 3rd December each year. Promptly.
MaxwellBuchanan, Dec 11 2018
  

       We had not quite factored in your rather unscrupulous approach to commercial arrangements. In retrospect, that was a very serious oversight, and one we don't intend to repeat. It's one thing to have // the small print // in a very small, closely spaced font such that a magnifying glass is needed. We even checked the contract for microdots, invisible ink, magnetic lines hidden in the normal printing, and barcodes made with radioisotopes.   

       Engraving the extra-small print on the edge of the paper using a scanning tunneling electron microscope was, however, truly inspired.
8th of 7, Dec 11 2018
  

       Ah. So you've not yet found the _extra_ small print then. Oh good.
MaxwellBuchanan, Dec 11 2018
  

       On re-reading.   

       //It's not fun though//   

       Confused about what your point was.   

       Neither is life threatening tissue rejection of a major organ.   

       I wouldn't imagine a lifetime spent on immune system suppressing drugs is a whole barrel of laughs either.
Skewed, Dec 16 2018
  

       Maybe not a whole barrel, but a rather fuller barrel than the one associated with dying from a lack of immune suppression.
8th of 7, Dec 16 2018
  

       ^ that is what I said, more or less my point restated :)
Skewed, Dec 16 2018
  

       "Extensive studies of organ and tissue tolerance induction via bone marrow transplantation were carried out.."   

       hmm? : the article is beginning to swim around as partially (or is that largely?) incomprehensible word salad for me, so I may be taking that slice of salad out of context, but is this article <link> talking about the same thing (or bits of the same thing) do you think?
Skewed, Dec 31 2018
  

       //talking about the same thing (or bits of the same thing) do you think?//   

       It's in the same ballpark. That's not a very well written article, which is disappointing because good writing is vital when trying to convey understanding. Maybe they avoided good writing because there was no understanding to convey? I think the problem is quite general, immunology is tricky.   

       Anyhow, I guess the part that caught your attention is the first sentence and reference to the 1954 Nature paper, i.e. that you can inject foreign cells shortly after birth and they will be tolerated. So you can make a tolerant immune system. Bear in mind that this is mouse-mouse, not across species. Also bear in mind that lab mouse strains are incredibly inbred, very close genetically.   

       The basic problem remains though, once you make a tolerant immune system, you have to get it into your recipient. To do that, refer to the first line of section 2.   

       "Initial studies of tolerance induction through mixed chimerism involved lethal irradiation..."   

       They irradiated the mice, added in foreign immune cells and they subsequently became immune chimaeras, i.e. some host, some donor cells for the rest of their presumably short lives. So they killed the mice but didn't completely get rid of the host immune system. You have to try really hard to clear that out. No matter how you go about it, it's very very nearly lethal. If you already have kidney failure, that's likely a bridge too far.   

       Probably a better strategy, is to have a line of clonal pigs and then routinely inject neonatal humans with pig cells to induce tolerance. Then, when an organ is needed you go to your clonal pig-organ farm* and get one. A lot less backwardsing and forwardsing.   

       The steps you would need to get that done are not trivial, however. You'd need to demonstrate that you can produce pig tolerant immunity in humans (good luck getting volunteers & Ethics approval) then you need to wait for an organ failure (the early ones will be say, 40 years into the study). Now you can do your transplant and about 5-10 years later asses the viability of the strategy. That's a long turnaround time.   

       *it would make sense that you get the rest of the pig free, a juicy pork chop would be a tasty transplant recovery meal. Would it technically be cannibalism though?
bs0u0155, Dec 31 2018
  

       //I guess the part that caught your attention is the first sentence and reference to the 1954 Nature paper//   

       Actually it was the bit much further down that caught my eye (the bit regarding bone marrow transplants in pigs that I quoted below the link) & seemed (potentially) close to what I was thinking of.   

       The mouse bit when you read on appeared to have disappointingly conflicting results, but I drew some comfort from the fact those mouse studies appear to be talking about post-birth injections rather than in-womb pre-birth injections to the developing fetus.   

       //not a very well written article//   

       Oh good, I was worried it was just me :)   

       //Probably a better strategy//   

       Yep, that's the idea that spawned this one (see 1st link).   

       //good luck getting volunteers & Ethics approval//   

       Oh yes indeed, one reason I was rooting around my mostly empty cranial space for a different idea.   

       Ethics committees might have an easier time with this one, turn around of proof of concept (or failure) should be quicker & if this flew getting the first one past ethics committees might conceivably be easier.   

       //good luck getting volunteers//   

       But for this one? if initial animal trials (transplants from sheep to pigs perhaps) where sufficiently successful it's not entirely implausible I'd be happy volunteering myself for the human trial stage (if I felt it was properly organised & funded), for a share of the eventual patent of course, I think you could find volunteers for this one, there are after all plenty of mildly unstable nutters out there :)
Skewed, Dec 31 2018
  

       Braking News: "Cancer drugmaker Bristol-Myers Squibb said it would buy Celgene for about $74 billion"   

       Aren't they supposed to be an anti-cancer drugmaker?
not_morrison_rm, Jan 03 2019
  

       //Aren't they supposed to be an anti-cancer drugmaker?//   

       Shhh! you're not supposed to talk about that, but if you're making drugs that damage DNA and mess about with replicative hardware then there's a good chance you'll make a few cancerous mistakes. Saying that they don't seem to have anything particularly nasty in their portfolio. Although how a big name pharma company can have garden-variety metformin in their product list with a straight face is beyond me.
bs0u0155, Jan 03 2019
  

       // drugs that damage DNA and mess about with replicative hardware then there's a good chance you'll make a few cancerous mistakes. //   

       <Obligtory Ethyl Methane Sulphonate reference/>   

       // incredibly inbred, very close genetically //   

       Well, at least it's a workable technique for [MB]'s family ...
8th of 7, Jan 03 2019
  


 

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