Big Tongues and Extra Vertebrae: The Unintended Consequences of Animal Gene Editing
Big Tongues and Extra Vertebrae: The Unintended
Consequences of Animal Gene Editing
Unintended consequences have included enlarged rabbit
tongues and extra pig vertebrae, as bioethicists warn of hubris
An experiment in China to change the colors of Merino
sheep gave some spotted fleeces akin to a panda.
By Preetika Rana and Lucy Craymer Dec. 14, 2018 12:35
p.m. ET
The purported birth last month of the world’s first
gene-edited human babies, claimed by a Chinese scientist, spurred a wave of
global outrage. Scientists denounced the (as yet unconfirmed) experiment as
irresponsible, and the development reinforced fears that the redesigning of DNA
is moving ahead too fast and without necessary oversight.
The proliferation of similar experiments on farm animals
in recent years supports those concerns. Though rapid strides have been made to
map genomes—the full set of genes for humans, animals, insects and
plants—scientists have only begun to understand what the tens of thousands of
individual genes do. Moreover, they are far from unraveling how those genes
interact with each other.
Scientists around the world are editing the genes of
livestock to create meatier pigs, cashmere goats with longer hair and
cold-weather cows that can thrive in the tropics. The goals are to improve
agricultural productivity, produce hardier beasts and reduce practices that are
costly or considered inhumane. But amid some successes, disturbing outcomes are
surfacing.
‘Even the genes
that we think we know very well, there’s a lot to learn.’ —geneticist Se-Jin
Lee
When Chinese researchers deleted a gene that limits
muscle growth in mammals so that rabbits would grow leaner, their creations
exhibited an unusual characteristic: enlarged tongues. Similar experiments on
Chinese pigs led some to develop an additional vertebrae. Gene-edited calves
died prematurely in Brazil and New Zealand.
The stumbles show the risks of racing ahead with such
experiments, even as many governments work to clear regulatory pathways to
bring meat, eggs and dairy from gene-edited animals to store shelves.
Bioethicists and many geneticists have raised doubts about applying the
gene-editing technology to animals and especially humans, given the continued
uncertainties in both the science and the lab and field results.
“Humans have a very long history of messing around in
nature with all kinds of unintended consequences,” said Lisa Moses, an animal
bioethicist at Harvard Medical School’s Center for Bioethics. “It’s really
hubris of us to assume that we know what we’re doing and that we can predict
what kinds of bad things can happen.”
The belief has spread that scientists know how gene
editing works “all the time, under all conditions,” says Odd-Gunnar Wikmark, a
researcher at the Norway-based foundation GenOk, which studies the consequences
of genetic engineering. “We of course do not.”
Critics say that editing animal DNA could introduce
unwanted mutations that pose a threat to human health when consumed, and they
fear that mutated genes may spread unchecked as animals breed. Proponents say
they are engineering mutations just as traditional crossbreeding does, only
faster. Though no gene-edited animal products have reached markets yet, the
potential benefits to farming have led many big agricultural nations to join
the race.
Crispr-Cas9, the tool introduced in 2012 that was used to
engineer the human babies, is cheaper than older techniques and enables
scientists to add, delete and rearrange DNA with greater precision. But an
article published in the journal Nature Biotechnology in July suggests that
Crispr might cause greater damage than previously understood—including changes
in genes other than those intended. When DNA is cut, “a lot of odd things can
happen,” study leader Allan Bradley said in July.
Take the gene called MSTN. Since 2012, Kui Li, a
scientist with the state-run Chinese Academy of Agricultural Sciences, has
reverse-engineered cells from adult Chinese pigs to their embryonic stage,
which is a common process when cloning animals. Then, using an older editing
tool, he deleted MSTN, which limits how large muscles grow in mammals, including
in humans. The edited cells are infused into eggs, chemically fertilized in a
lab and implanted into the womb of a surrogate. At a farm 70 miles southeast of
Beijing, dozens of pigs rest in metallic cages and glass enclosures; their meat
is up to 12% leaner if both copies of their MSTN gene are deleted.
But there was another effect on the pigs: One in five
offspring who inherited the edited genes had an extra spinal bone known as
thoracic vertebrae, Dr. Li found. He doesn’t know why, though he postulates
that the MSTN gene somehow contributes to skeletal formation. Lab tests show
that his pigs are safe to eat, said Dr. Li: Despite a slight fading in color
after cooking, he recorded no nutritional differences. He’s begun using Crispr
to make more commercial breeds like the U.K.’s Large White leaner or resistant
to PRRS, a deadly viral infection.
When state-sponsored scientists at Nanjing Agricultural
University used Crispr to edit MSTN out of rabbits to make them meatier, 14 of
the 34 engineered offspring were inexplicably born with enlarged tongues,
leading the scientists to warn of abnormalities from gene editing in a 2016
research paper on their project. “Safety issues need to be addressed in future
studies before the technology can be utilized” in agriculture, the authors
wrote.
“Even the genes that we think we know very well, there’s
a lot to learn,” said Se-Jin Lee, one of the scientists who discovered MSTN at
the Johns Hopkins University School of Medicine in 1997.
Chinese scientists at a different research facility have
had to use caesarean sections to birth lambs whose MSTN genes were deleted with
Crispr, because some grew too large to be birthed naturally. They have had
success modifying goats’ cashmere to grow about 20% longer by preventing the
gene FGF5 from regulating the growth.
Generally, the larger the animals, the greater the
complications. New Zealand’s AgResearch Ltd. applied Crispr on cattle to reduce
their heat stress, deleting a single amino acid on a gene that contributes to
coat color (including hair and skin color in humans), in an effort to lighten
the cows’ black-and-white coats to better reflect sunlight. Both calves died
(one was sick and was euthanized). In a separate experiment using an older tool
to enable cold-weather Angus cattle to thrive in the Brazilian tropics, one of
two calves died prematurely.
Scientists in both experiments blame cloning, which
created the calves but still isn’t foolproof, they say, after two decades in
use. Neither is their understanding of genes. “But if we don’t try, we will
never learn,” said Goetz Laible, who led AgResearch’s experiment.
Globally, at least a dozen gene-edited livestock projects
are aiming to reach consumer markets. Some may face less resistance from
consumers and ethicists because they could eliminate reviled practices: Cattle
could be engineered without horns, for instance, obviating the need to dehorn
them.
Wool from a gene-edited animal might also be more readily
accepted because it is only worn, not eaten. Researchers in China’s eastern
Xinjiang region used Crispr to alter the ASIP gene, believed to influence coat
color in Merino sheep, with the aim of creating new breeds with darker
coats—all black, gray or brown—so that off-white wool wouldn’t need to be dyed.
The results confirmed previous research suggesting that
genes involved in coat color also play a role in reproduction: Only a fourth as
many ewes implanted with the disrupted genes carried to term, as compared to
normal circumstances. Meanwhile, for the wool itself, the results were mixed:
One sheep was white, two were mostly black, and the other three had spotted
fleeces akin to a panda.
The outcome also underlined how far there is to go in understanding
the forces at work among the genes of humans and animals. “I think it would be
an understatement to say we should be more cautious,” said Lori Marino, a
neuroscientist and the founder of Utah-based Kimmela Center for Animal
Advocacy. “I think we’ve already gone over the line with animals, and now
humans.”
—Zhou Wei contributed to this article
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