Seventeen people in the US die every day
waiting for an organ transplant, usually a kidney.
You would think that at the rate of two per person,
we’d have enough of those to go around, but clearly we don’t.
Scientists would love to create their own kidneys using animals,
to close the gap with human organ donors.
Which is why it caught our attention when we read about
a group that’s trying to grow human kidneys in pigs.
There are serious challenges to this approach… technical, and ethical.
But here’s how it might work.
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The amount of donated kidneys that we have,
and the amount that we would like to have, are very different numbers.
Not everyone signs up to be an organ donor.
Maybe they believe the scary myth that doctors
won’t work as hard to save their lives.
Just fyi, it’s totally different people making that decision, not your trauma team.
Or maybe people just don’t know you can sign up to donate a kidney
or a bit of your liver while still alive.
Cheeky link in the description if that’s something you maybe wanna sign up for.
There can also be logistical barriers to getting donated organs
to the people who need them in time, but that is outside the scope of this video.
And there are other issues.
Even if someone’s an organ donor, they might not die in a way
that allows procuring of their organs.
And not all of us can part with a kidney voluntarily, though again,
if you wanna be a hero, that is a thing.
This is where the pigs come in.
A team of researchers created and grew combination pig and human kidneys
in pig embryos using stem cells from human umbilical cord blood,
and published their results in the journal Cell Stem Cell in September of 2023.
It is a first-of-its-kind feat.
And if that didn’t seem weird enough, other researchers are
taking an opposite approach: making pig kidneys just human enough.
Research on xenotransplantation, or transplanting organs and tissues
from non-human animal sources into humans,
has been advancing over the past decade.
Scientists had already grown human cells in other animals,
including rats and mice, and humanoid tissues like cartilage in pigs.
But this research represents the closest we’ve come
so far to growing solid, humanized organs in pigs.
If it works in the long run, it brings us closer to what some scientists call
a holy grail for regenerative medicine.
Most of us probably associate pigs with summer barbeques or Stardew Valley.
And even though there are reasons they’re our
model of choice for this kind of research, it’s still pretty tricky.
Non-human primates would work a lot better than pigs,
since they’re genetically similar to us.
But for both legal and ethical reasons,
we’re moving away from using primates for research.
So we have to move on to other options.
Pigs are relatively similar in size to humans,
and their organs are set up in similar ways.
Also, we know how to raise a lot of them at this point.
Yes, even outside of farm games.
But it’s not that simple.
It’s not just size and anatomy that matter.
Research suggests that, the more closely genetically related two species are,
the better their cells will be able to grow side by side without rejection.
Humans are more genetically similar to mice than pigs,
and experiments have suggested that
pig and human cells just don’t like to play nice.
Part of the reason for that is that pig embryos develop faster
than human embryos, so they’re developmentally out of sync with each other.
But a research team is working on tackling each of those issues,
in order to use pigs to grow human organs.
In that 2023 paper, the researchers engineered a chimeric human-pig kidney
with human cells that could basically outcompete the pig cells as the organ grows.
Chimerism refers to any time you’ve got cells with different genomes going on.
And it basically worked.
For a while, that is; for ethical and procedural reasons,
they planned to terminate their experiments early in fetal development.
The key was using induced pluripotent stem cells, also known as iPSCs.
iPSCs are, first of all, stem cells.
These are the key types of cells that allow the
development of an organism to happen.
They have the potential to become nearly any kind of cell,
whether you need to make a brain or a heart or a kidney.
The induced part means the researchers made these cells from other,
more mature cell types, sending them back to
cellular babyhood to make whatever they needed.
But that’s only the first part.
To get the stem cells to make kidneys,
the researchers had to create a suitable host niche.
This is basically the specialized environment in the living body where
stem cells reside and wait to differentiate depending on the need of the day.
These niches naturally exist in both embryonic development
and in certain sites in adult connective tissues.
The team had to give their human stem cells a couple of legs up to be
able to grow where pig cells would normally.
They grew the cells in a specialized solution that
helps keep them stem-y instead of differentiating into mature tissue.
They also ramped up two genes associated with
cellular survival to keep them kicking.
Now, in molecular biology, what’s good for
the goose isn’t always good for the gander.
These genes are involved in processes that tell cells to grow
and keep them from dying.
In embryonic development, you want that.
But those exact same processes are also involved in cancer,
so these are genes you want to use very, very carefully.
But at any rate, this means the researchers had their
human stem cells ready to make kidneys in a place they normally wouldn’t.
Then they basically took pig embryos, tweaked the pig cells
to skip kidney formation, added these extra-rugged human stem cells,
and implanted their embryos in sows.
About a month later, the sows were pregnant with pig embryos with… well,
not quite full kidneys, because kidney development is wild in that they
stop and start over, like, twice.
But part-human, part-pig… part-kidneys.
The researchers collected the embryos and found that
the proto-kidneys were made up of about half human cells.
Some experts who weren’t involved in the research have said that
the proportion of humanized cells is still too low.
Also me, I am not an expert but that seems like a low amount to me.
What’s more, only a very small fraction of implanted embryos survived.
Which means this approach is nowhere near ready to go yet,
from a purely scientific perspective.
But researchers say it opens up an exciting avenue for regenerative medicine,
as well as an artificial means for studying human kidney development.
Now, this is pretty wild.
But there’s another research group out there embracing
the essence of “keep it simple, stupid.”
Instead of a human kidney grown in a pig, scientists working for the
NYU Langone Transplant Institute transplanted kidneys from
genetically modified pigs into two brain dead human patients.
These researchers obtained explicit permission from the families of the recipients,
who had donated their bodies to scientific research.
Most mammals that aren’t primates express
a marker on their cells called alpha-gal.
Since our cells never have the stuff, our immune systems respond to it like
a five-alarm fire, causing rejection of animal tissue within minutes to hours.
Sensitization to this same molecule can cause a red meat allergy in humans,
including those bitten by certain types of ticks that carry it in their saliva.
The researchers basically knocked out this single gene
in the pig so that a human host won’t reject its tissue.
They also grafted a part of the pig's thymus inside of the kidney ahead of time.
This is a small gland in mammals and certain other vertebrates involved in
the production of T cells, a type of white blood cell that fights off foreign invaders.
The thymus is also involved in the destruction of T cells, and some research
has shown that when a piece of thymus is grafted to a donor kidney,
it works to prevent the immune system from attacking the organ.
The alpha-gal knockout worked.
In their most recent attempt at time of writing, one of the kidneys functioned for
61 days without being rejected, at which point
the researchers concluded the experiment.
The thymus graft may have also had something to do with this success,
or it might have just been the alpha-gal.
The researchers aren’t totally sure.
Which really begs the question of why you’d
mess around with that other thing, right?
Knock out one gene and we’ve got all the kidneys we need!
Well, it probably isn’t that simple.
Two months is great, but donated organs usually last around a decade.
The thymus graft is supposed to increase immune tolerance,
but we’ll need to see that happen over a long period of time to believe it.
And there may be some advantages to the iPSC-based approach.
You can make iPSCs from a patient’s own cells, which could mean we’d be
able to sort of clone a kidney for a person using a pig;
a kidney that’s pretty much genetically identical to their own cells.
And the researchers say it’s also a way to study the development of human
kidneys, even when the approach isn’t being used to produce donor organs.
So yeah, we’ve established that you can probably grow humanoid organs in pig
embryos, and that genetically engineered pig organs can function in human bodies.
But we would be remiss to gloss over the age-old sentiment made famous
by old stories like Frankenstein and Jurassic Park:
without really, really robust safeguards, what if things get out of hand?
Some parties argue that research into induced chimerism and xenotransplantation
is unethical in certain circumstances,
while others say it’s inherently unethical regardless of the consequences.
Their reasoning is based on unease about mixing human and animal tissue.
What human characteristics might they acquire?
Could they reproduce? Would they be smart, like us?
These concerns aren’t necessarily likely, and a pig grown for its human-based
kidneys is not going to stand up and start reciting Hamlet.
But it’s still something researchers should account for.
And the authors of the chimeric kidney study noted that they found a couple of
human cells in the pig embryo brains.
Only a couple, but that’s still a part-human brain if you squint.
They think they can fix this by knocking out genes in the human cells,
but worry it could cause problems in the growing kidney.
Another major ethical concern is that animals’ rights would be in question in
a way that’s distinct from killing them for meat,
which is its own huge can of worms.
And this goes for any approach where we’re
using organs grown in nonhuman animals.
See, doctors have a responsibility to protect patients from the risk of zoonotic,
or animal-transmitted, disease.
Patients have a right to receive an organ that
won’t make them sicker instead of making them better.
In particular, there’s this sort of fossilized virus that lives in pig DNA,
called Porcine Endogenous Retrovirus or PERV (yes, really)
that could hypothetically wake up and cause problems on purpose.
That means keeping pigs under very different conditions than what you’d see
on a farm: restraining them, monitoring them frequently,
and keeping them isolated.
Like us, pigs are social animals.
To protect patients’ rights and safety, you’re creating what some scholars
have called unacceptable circumstances for raising those animals.
And one further wrinkle: for all medical research,
you have to obtain informed consent, meaning you have to
tell patients what they can expect, and they have a right to opt out.
If you put an organ in someone, and then you have to monitor that organ to see
if any zoonotic diseases manifest, for life, that person can’t opt out, can they?
The researchers who performed the alpha-gal transplants say that
the risk of zoonotic disease is probably really low because
there have been no recorded cases of PERV being transmitted to humans.
Further research and clinical trials will elucidate
these risks before any of this happens on a large scale.
Finally, while pigs have their advantages and disadvantages,
this research doesn’t do a lot to account for
the worldwide prevalence of pork taboos.
Sure, faith leaders and communities might decide that saving a life is worth
breaking that taboo, but by doing all this in pigs, you’re asking them to do that.
So, both technical and ethical hurdles still abound before pigs can be used
as a major supply of organs for human transplantation.
But scientists don’t dispute that the new developments are a major step toward
getting humanity’s hands on the holy grail of an unlimited organ supply.
As always, remember that this is an internet video.
We’re not on here to deliver a final answer on
whether those pursuing this grail should be doing so.
But this research is absolutely fascinating, even if it does seem pretty out there.
One thing’s clear: progress in this field could save human lives,
and everyone agrees that’s a goal worth pursuing.
For now, organ donation’s still the best that we can do,
but I’m looking forward to the day that that changes.
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