Scientists create a
part-human, part-pig embryo — raising the possibility of interspecies organ
transplants
For the first time,
scientists have grown an embryo that is part-pig, part-human.
The experiment, described
Thursday in the journal Cell, involves injecting human stem cells
into the embryo of a pig, then implanting the embryo in the uterus of a sow and
allowing it to grow. After four weeks, the stem cells had developed into the precursors
of various tissue types, including heart, liver and neurons, and a small
fraction of the developing pig was made up of human cells.
The
human-pig hybrid — dubbed a “chimera” for the mythical creature with
a lion's head, a goat's body and a serpent's tail — was “highly
inefficient,” the researchers cautioned. But it's the most successful
human-animal chimera and a significant step toward the development of
animal embryos with functioning human organs.
In a study published a day
earlier, an international team of researchers demonstrated that organs for
transplant can be grown in chimera embryos that are part-mouse, part-rat.
Writing in Nature,
the researchers reported Wednesday that they were able to grow a mouse
pancreas inside a rat embryo, then transfer insulin-secreting tissue from that
organ into diabetic mice, alleviating their illness without triggering an
immune response.
It was the first
demonstration that such an interspecies organ transplant is possible.
Researchers hope that one day doctors may be able to grow human tissue
using chimera embryos in farm animals, making organs available for sick
humans who might otherwise wait years for a transplant.
The technique is already
the subject of a vigorous debate about the ethics of introducing human
material into animals; since 2015, the National Institutes of Health has
had a moratorium on funding for certain human-animal chimera research.
(The new study was
performed in California at the Salk Institute without federal funds.)
Some argue that, since
stem cells can become any kind of tissue, including parts of the nervous
system, chimeras raise the specter of an animal with a human brain
or reproductive organs.
Others think there's a
symbolic or sacred line between human and animal genetic material that should
not be crossed.
But Vardit Ravitsky, a
bioethicist at the University of Montreal's School of Public Health, said that
the two studies published this week could help make a case for further
human-animal chimera research by demonstrating the field's potential
benefits.
“I think the point of
these papers is sort of a proof of principle, showing that what researchers
intend to achieve with human-non-human chimeras might be possible,” she said.
“The more you can show that it stands to produce something that will actually save
lives … the more we can demonstrate that the benefit is real, tangible and
probable — overall it shifts the scale of risk-benefit assessment, potentially
in favor of pursuing research and away from those concerns that are more
philosophical and conceptual.”
In an effort to address
the world's growing organ shortage — an estimated 22 people a day die waiting
for transplants, according to the U.S. Department of Health and Human
Services — scientists have been trying to grow organs
outside the human body. But organs developed in petri dishes are not identical
to the ones that grow inside a
living thing.
“That's where the
rationale of this kind of experiment comes in,” said Juan
Carlos Izpisua Belmonte, a developmental biologist at the Salk
Institute and the senior author on the study of the human-pig chimera.
“What if we let nature do
the work for us? What if we just put human cells inside the embryo and the
embryo knows what do to?”
The model for using
chimeras for organ transplant would probably look something like the technique
reported in Nature. In that experiment, researchers took induced
pluripotent stem cells (ordinary
cells that have been reverted to an early embryonic state, so that they have
the potential to develop into any tissue type) from mice. These cells were then
injected into rat embryos that had been genetically modified so that
they were unable to grow their own pancreas — “emptying a niche” for the
mouse stem cells to fill.
The embryonic rats
developed normally and were born healthy. Each had a rat-sized pancreas made of
mouse cells. The whole pancreases were too big to transplant into tiny mice, so
the researchers extracted just the islets — the region of the pancreas that
produces hormones like insulin — and planted them in mice that had been induced
to have diabetes.
Because the transplanted
cells were grown from stem cells taken from mice, the animals required just
five days of immunosuppressive drugs to keep their bodies from rejecting the
new tissue. After that, they were able to live normally with healthy blood
glucose levels for over a year — half a lifetime in human terms.
The study showed that
interspecies organ transplants are not only possible, but they can be done
effectively and safely, said Hiromitsu
Nakauchi, a stem cell researcher at Stanford University and the
University of Tokyo who is the senior author of the study.
“This is a form of
transplantation we could do in the clinic with human patients someday,” he
said.
Nakauchi also conducts
research on human-chimera embryos, but his efforts to inject human stem cells
into sheep embryos have largely been unsuccessful — the evolutionary
distance between humans and livestock may be making it difficult to get
human stem cells to take hold in those animals.
Other researchers
have achieved human-mouse chimeras that developed to full size and grew to adulthood, but there is
debate about how substantially human cells can contribute to mice, which are
much more distantly related.
He said he was cheered to
read the Cell study, which represents the most significant progress on
human-animal chimeras yet, though the technique is still nowhere near ready for
an experiment like the one performed in Nakauchi's mice.
“If you read the
paper, the contribution of human cells is very limited, is very, very minor,
and only in the early embryonic phase, so we’re still not sure if we can make
human chimeras,” he cautioned. “But I'm glad that they're doing this research.”
The Cell study
was the result of four years of work involving some 1,500 pig
embryos. These embryos were not genetically modified, like Nakauchi's rat
embryos, but the Salk scientists used a similar technique to inject human stem
cells.
Pigs are an ideal animal
for chimera research, said co-author Pablo Ross, an associate
professor in the department of animal science at the University of California,
Davis. Their organs are roughly the same size as those of humans (recall that
the pancreases grown in Nakauchi's rats were rat-sized, even though they were
grown with mouse cells), but they reach their full size far more quickly than
humans and other primates.
“You go from one cell [at]
fertilization to 200 pounds, the average size of an adult [pig], in
nine months,” Ross said. “I think that's very reasonable, when you think
about the fact that the average wait for a kidney transplant is about
three years.”
Still, pigs' rapid
gestation means that their organs develop much more rapidly than those of
humans. If researchers want to create a successful chimera, they have
to consider timing.
So Ross and his colleagues
used three different types of stem cells for their experiment: “naive” cells
that were at the very earliest stages of development, “primed” cells that have
developed further (but are still pluripotent), and “intermediate” cells that
are somewhere in between.
Dozens of cells of each
type were injected into pig embryos, which were then implanted in sows and allowed
to develop for three to four weeks (about a quarter of a pig's gestation
period). The primed cells never really took hold in the host embryo. The naive
cells were initially incorporated into the growing animal, but were
indistinguishable in the developing pig four weeks later.
The intermediate cells
were most successful; by the time the embryos were removed from the sow
and analyzed, about one in every 100,000 cells was human rather than pig, lead
author Jun Wu estimated. The human cells were
distributed randomly across the chimera: Many wound up in what would become the
heart (where they made up about 10 percent of tissue), some in the kidneys and
liver (1 percent or less).
A few developed into the
precursors of neurons, a fear of bioethicists who worry about creating an
animal with human or even humanlike consciousness.
But Izpisua Belmonte said
that prospect is still a long way off. The contribution of human cells to the
chimera was tiny, and research protocols were in place to prevent the
development of any human-animal chimera to maturity.
“We were just trying to
answer the yes or no question of, can human cells contribute at all?” he said.
“And the answer to that question is yes.”
The Cell study researchers
also discussed progress with rat-mouse chimeras. Though they have not
performed an interspecies organ transfer, they were able to grow hearts, eyes
and pancreases in chimeric embryos.
They also grew a rat gall
bladder inside a mouse embryo, even though rats don't grow gall bladders during
normal development — suggesting that rats have the genetic coding for gall
bladders but those genes are suppressed by their developmental environment.
That's another important
aspect of chimera embryo research, Izpisua Belmonte said, one that is
sometimes overlooked in the focus on organ transplants. Chimera embryos can be
used to understand development, examine genetic diseases and test
drugs without risking the health of humans.
In August, NIH released a
draft of a policy that
would change the guidelines to allow funding of certain human animal chimeras.
Under the proposed new rule, the taxpayer funds could be used for
experiments that introduced human stem cells to early stage embryos of all
animals except other primates. Some nonhuman primate research would also be
allowed, but only using embryos at later stages of development and only after
an extra layer of review by a special NIH committee. But the policy change is
still under review.
Neither Nakauchi's nor
Izpisua Belmonte's study was funded by NIH grants. Nakauchi said he hoped
that recent progress in the field might garner support for easing the ban.
“Finally we’re able to
provide a proof of principle that ... this approach of making organs … is
possible and also safe and efficient,” he said. “So I hope people will
understand this.”
He continued, “Many people
think this is a kind of science fiction story. But this is becoming reality.”
Source: Washington Post News
