Chinese scientists genetically modify human embryos
Chinese scientists genetically modify human embryos
Rumours of germline modification prove true — and look
set to reignite an ethical debate.
By David Cyranoski & Sara Reardon
22 April 2015
Human embryos are at the centre of a debate over the
ethics of gene editing.
In a world first, Chinese scientists have reported
editing the genomes of human embryos. The results are published1 in the online
journal Protein & Cell and confirm widespread rumours that such experiments
had been conducted—rumours that sparked a high-profile debate last month about
the ethical implications of such work.
In the paper, researchers led by Junjiu Huang, a
gene-function researcher at Sun Yat-sen University in Guangzhou, tried to head
off such concerns by using 'non-viable' embryos, which cannot result in a live
birth, that were obtained from local fertility clinics. The team attempted to
modify the gene responsible for β-thalassaemia, a potentially fatal blood
disorder, using a gene-editing technique known as CRISPR/Cas9. The researchers say
that their results reveal serious obstacles to using the method in medical
applications.
"I believe this is the first report of CRISPR/Cas9
applied to human pre-implantation embryos and as such the study is a landmark,
as well as a cautionary tale," says George Daley, a stem-cell biologist at
Harvard Medical School in Boston. "Their study should be a stern warning
to any practitioner who thinks the technology is ready for testing to eradicate
disease genes."
Some say that gene editing in embryos could have a bright
future because it could eradicate devastating genetic diseases before a baby is
born. Others say that such work crosses an ethical line: researchers warned in
Nature2 in March that because the genetic changes to embryos, known as germline
modification, are heritable, they could have an unpredictable effect on future
generations. Researchers have also expressed concerns that any gene-editing
research on human embryos could be a slippery slope towards unsafe or unethical
uses of the technique.
The paper by Huang's team looks set to reignite the
debate on human-embryo editing — and there are reports that other groups in
China are also experimenting on human embryos.
Problematic gene
The technique used by Huang’s team involves injecting
embryos with the enzyme complex CRISPR/Cas9, which binds and splices DNA at
specific locations. The complex can be programmed to target a problematic gene,
which is then replaced or repaired by another molecule introduced at the same
time. The system is well studied in human adult cell and in animal embryos. But
there had been no published reports of its use in human embryos.
Huang and his colleagues set out to see if the procedure
could replace a gene in a single-cell fertilized human embryo; in principle,
all cells produced as the embryo developed would then have the repaired gene.
The embryos they obtained from the fertility clinics had been created for use
in in vitro fertilization but had an extra set of chromosomes, following
fertilization by two sperm. This prevents the embryos from resulting in a live
birth, though they do undergo the first stages of development.
Huang’s group studied the ability of the CRISPR/Cas9
system to edit the gene called HBB, which encodes the human β-globin protein.
Mutations in the gene are responsible for β-thalassaemia.
Serious obstacles
The team injected 86 embryos and then waited 48 hours,
enough time for the CRISPR/Cas9 system and the molecules that replace the
missing DNA to act — and for the embryos to grow to about eight cells each. Of
the 71 embryos that survived, 54 were genetically tested. This revealed that
just 28 were successfully spliced, and that only a fraction of those contained
the replacement genetic material. “If you want to do it in normal embryos, you
need to be close to 100%,” Huang says. “That’s why we stopped. We still think
it’s too immature.”
His team also found a surprising number of ‘off-target’
mutations assumed to be introduced by the CRISPR/Cas9 complex acting on other
parts of the genome. This effect is one of the main safety concerns surrounding
germline gene editing because these unintended mutations could be harmful. The
rates of such mutations were much higher than those observed in gene-editing
studies of mouse embryos or human adult cells. And Huang notes that his team
likely only detected a subset of the unintended mutations because their study
looked only at a portion of the genome, known as the exome. “If we did the
whole genome sequence, we would get many more,” he says.
Ethical questions
Huang says that the paper was rejected by Nature and
Science, in part because of ethical objections; both journals declined to
comment on the claim (Nature’s news team is editorially independent of its
research editorial team.)
He adds that critics of the paper have noted that the low
efficiencies and high number of off-target mutations could be specific to the
abnormal embryos used in the study. Huang acknowledges the critique, but
because there are no examples of gene editing in normal embryos he says that
there is no way to know if the technique operates differently in them.
Still, he maintains that the embryos allow for a more
meaningful model — and one closer to a normal human embryo — than an animal
model or one using adult human cells. “We wanted to show our data to the world
so people know what really happened with this model, rather than just talking
about what would happen without data,” he says.
But Edward Lanphier, one of the scientists who sounded
the warning in Nature last month, says: "It underlines what we said
before: we need to pause this research and make sure we have a broad based
discussion about which direction we’re going here." Lanphier is president
of Sangamo Biosciences in Richmond, California, which applies gene-editing
techniques to adult human cells.
Huang now plans to work out how to decrease the number of
off-target mutations using adult human cells or animal models. He is
considering different strategies — tweaking the enzymes to guide them more
precisely to the desired spot, introducing the enzymes in a different format
that could help to regulate their lifespans and thus allow them to be shut down
before mutations accumulate, or varying the concentrations of the introduced
enzymes and repair molecules. He says that using other gene-editing techniques
might also help. CRISPR/Cas9 is relatively efficient and easy to use, but
another system called TALEN is known to cause fewer unintended mutations.
The debate over human embryo editing is sure to continue
for some time, however. CRISPR/Cas9 is known for its ease of use and Lanphier
fears that more scientists will now start to work towards improving on Huang's
paper. “The ubiquitous access to and simplicity of creating CRISPRs," he
says, "creates opportunities for scientists in any part of the world to do
any kind of experiments they want.”
A Chinese source familiar with developments in the field
said that at least four groups in China are pursuing gene editing in human
embryos.
Nature doi:10.1038/nature.2015.17378
References
1.Liang, P. et al. Protein Cell
http://dx.doi.org/10.1007/s13238-015-0153-5 (2015).
2.Lanphier, E. et al. Nature 519, 410–411 (2015).
3.Baltimore, D. et al. Science 348, 36–38 (2015).
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