h a l f b a k e r yI think this would be a great thing to not do.
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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.
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/> |
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This seems like quite a drastic solution to a problem - all
this business about removing bone marrow. |
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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. |
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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. |
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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). |
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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. |
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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). |
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*Tinkering with pigs is still legal in the Irish Republic; it's one
of the less-discussed problems with Brexit. |
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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. |
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// Make sure the resulting child is anencephalic // |
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So what you're implying is that somewhere, the original of Justin Bieber is living quietly until one of his organs fails ? |
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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. |
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What you really need is a Version 1.1, with the majority of the significant bugs fixed. |
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// they're letting me have pointed crayons again next week // |
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//<Starts collecting sticks and kindling for when [bs0]
arrives and orders the roasting to commence// |
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So very kind, it's bloody freezing here. |
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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. |
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//Step three, remove patient A's bone marrow// |
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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. |
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//Step four, patient A now has an immune system that
recognizes both patient A's own cells & the pigs as what's
good..// |
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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. |
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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. |
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*not always the best choice, guardians of prevailing
wisdom are often close to retirement and therefore not
that invested. |
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//can't really remove bone marrow// |
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Don't they normally kill it off with chemotherapy before a
bone marrow transplant? ah yes, you said, so do that then. |
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//your pig immune system and bone marrow are going to
age badly, it's off by about 10 fold.// |
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That seems to mean humanized pig organs would suffer the
same fate, or is bone marrow a special case? |
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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. |
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//Except the pig is dead.// |
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Yes, we did say to put it in the fridge. |
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//they only live ~7 years// |
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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. |
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Or just start new clones every three years or so, then
there's always an adult available for harvesting. |
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//they only live ~7 years// |
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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. |
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//we really ought to focus on is a wide-ranging research
program centred around elephants// |
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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. |
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//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// |
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<nearly chokes to death laughing with a mouthful of food/> |
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//Don't they normally kill it off with chemotherapy
before a bone marrow transplant? // |
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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. |
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//pig cells aging faster really is a problem then just
humanize the bone marrow// |
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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? |
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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. |
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// So, what we really ought to focus on is a wide-
ranging research program centred around elephants.// |
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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. |
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//You then need to solve the problem of rejection// |
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Step one, we take a small sample of cells from patient A &
donor B & introduce these to a pig fetus.. |
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Step two & three, as above. |
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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. |
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// some sort of custom fork-lift will be needed to get the nozzles of the water bottles through the wire cage front // |
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What about an overhead crane ? |
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// but these aren't the sort of problems to discourage one unduly. // |
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Ever the optimist. You're overdoing the little green tablets again. |
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// ought to get [8th] developing a suitable guillotine // |
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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 ... |
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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... |
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// We're going to need a much bigger centrifuge. // |
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For separating the elephants from the anomalously-large great white sharks ? |
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//Except the pig is dead.// |
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Not until you open the box. Until then, it's in an indeterminate quantum state. |
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// So very kind, it's bloody freezing here. // |
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No problem, any unused stuff will go on the Buchanan family solstice bonfire. |
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//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. |
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//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. |
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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. |
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Engraving the extra-small print on the edge of the paper using a scanning tunneling electron microscope was, however, truly inspired. |
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Ah. So you've not yet found the _extra_ small print then. Oh
good. |
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Confused about what your point was. |
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Neither is life threatening tissue rejection of a major organ. |
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I wouldn't imagine a lifetime spent on immune system
suppressing drugs is a whole barrel of laughs either. |
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Maybe not a whole barrel, but a rather fuller barrel than the one associated with dying from a lack of immune suppression. |
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^ that is what I said, more or less my point restated :) |
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"Extensive studies of organ and tissue tolerance induction via
bone marrow transplantation were carried out.." |
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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? |
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//talking about the same thing (or bits of the same thing)
do you think?// |
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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. |
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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. |
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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. |
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"Initial studies of tolerance induction through mixed
chimerism involved lethal irradiation..." |
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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. |
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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. |
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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. |
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*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? |
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//I guess the part that caught your attention is the first
sentence and reference to the 1954 Nature paper// |
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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. |
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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. |
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//not a very well written article// |
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Oh good, I was worried it was just me :) |
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//Probably a better strategy// |
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Yep, that's the idea that spawned this one (see 1st
link). |
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//good luck getting volunteers & Ethics approval// |
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Oh yes indeed, one reason I was rooting around my mostly
empty
cranial space for a different idea. |
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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. |
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//good luck getting volunteers// |
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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 :) |
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Braking News: "Cancer drugmaker Bristol-Myers Squibb
said it would buy Celgene for about $74 billion" |
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Aren't they supposed to be an anti-cancer drugmaker? |
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//Aren't they supposed to be an anti-cancer drugmaker?// |
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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. |
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// drugs that damage DNA and mess about with replicative hardware then there's a good chance you'll make a few cancerous mistakes. // |
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<Obligtory Ethyl Methane Sulphonate reference/> |
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// incredibly inbred, very close genetically // |
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Well, at least it's a workable technique for [MB]'s family ... |
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