The
announcement that a Chinese team had altered the genetics of a human
embryo for the first time has ignited a firestorm of controversy around
the world and renewed recent calls for a moratorium on any attempt to
establish a pregnancy with such an engineered embryo. But it has also
underscored that although scientists are united in their opposition to
any clinical application of such embryo manipulation, they are split on
the value of basic research that involves genetically modifying human
embryos.
In China itself, where the precedent-setting research is big news and
some in the public have expressed concern on the Internet about the
embryo experiments, "most scientists are more positive," says Guo-Qiang
Chen, a microbiologist at Tsinghua University in Beijing. "My personal
opinion is that as long as they can control the consequences they should
continue this work.”
That viewed is echoed by many outside of China as well. “I personally
would defend the fundamental scientific value of research into gene
editing” in human embryos, in part to explore the risks of any potential
clinical use, George Daley, a stem cell biologist at Harvard Medical
School in Boston, tells Science.
The paper at the heart of the debate, published online on 18 April in Protein & Cell,
an obscure Chinese online journal published by an affiliate of China’s
Ministry of Education, drew widespread attention only after Nature News reported it online on
22 April. Junjiu Huang and colleagues at Sun Yat-sen University in
Guangzhou described how they attempted to use the CRISPR/Cas-9 system, a
new technology that makes it easy to modify genes in cells, to edit the
hemoglobin-B gene (HBB) in 86 human embryos donated for
research by couples at an in vitro fertilization (IVF) clinic. In
theory, this could be a way to prevent beta thalassemia, a blood
disorder that results when that gene is mutated, but the embryos
experimented on were selected because they were not viable; they had an
extra set of chromosomes as a result of being fertilized by two sperm.
Two days after being injected with gene-editing molecules, only four
of 54 surviving embryos that were tested carried the desired genetic
changes; these embryos were mosaic, meaning only some cells had the
intended changes. The edited embryos also had a large number of
off-target effects, or mutations in genes other than HBB, that could be potentially harmful.
The performance of the technique proved so poor that the researchers
emphasized that any clinical use of CRISPR/Cas9 for embryo editing is
“premature at this stage." The project was reviewed by Huang’s
university’s ethics board and complied with international and national
ethical standards, according to the paper. The researchers used abnormal
zygotes that would otherwise be discarded, “because ethical concerns
preclude studies of gene editing in normal embryos,” they write.
Still, the paper drew anger from some quarters. The Center for Genetics and Society in Berkeley, California, called for a halt to such experiments. Huang told Nature News that the paper was rejected by Science and Nature in part because of ethical concerns. (In an e-mail, Huang initially welcomed an inquiry from Science and asked for a list of questions by e-mail, but then he did not reply.)
Rumors that such a paper was in the works sparked several published opinion pieces a month ago. In a commentary in Science, molecular biologist David Baltimore, president emeritus of California Institute of Technology in Pasadena, and 17 co-authors called for scientists and others
to “strongly discourage … attempts at germline genome modification for
clinical application in humans.” (Many countries already ban germline
gene modification.)
Several scientists led by Edward Lanphier, CEO of Sangamo BioSciences in Richmond, California, went further in a Nature
commentary, calling for a voluntary moratorium on all experiments
involving germline gene modification. Although the two groups were “90%
in agreement,” they differed on this one point, Lanphier told Science: “We said let’s not perfect these technologies ahead of a conversation whether we should allow this technology.”
In contrast, two co-authors of the Science commentary say
that they are comfortable with the Huang experiment. Daley points out
that international guidelines developed by the stem cell researchers
allow for experiments with human embryos as long as the cells are not
allowed to grow for more than 14 days. “To further to inform any debate
on whether this technology could be useful for eradicating disease, one
has to understand the range of efficacy and off-target mutagenesis,”
Daley says.
Harvard molecular geneticist George Church agrees that the consensus
has long been that experiments on discarded IVF embryos are acceptable;
the only new thing is that the Huang group “used CRISPR, which makes it
noteworthy,” he says. Although he does not object to the the reported
experiment, Church adds that the results “were fairly predictable.” He
says one reason the researchers got so many off-target effects is
because they did not use the latest version of the gene-editing
technology.
But University of California, Berkeley, molecular biologist Jennifer Doudna, who organized a workshop that led to the Science
commentary, says her personal opinion is that the Huang experiment was
not necessary because scientists are still a long way from perfecting
the CRISPR gene-editing method. “I don't see the value in working with
human embryos right now. There’s a lot to be learned by working in other
systems,” she says. In her view, the Huang paper provided little new
scientific insight and seemed intended to “attract attention.” She is
also troubled that, according to the dates noted in the paper, Protein & Cell apparently published the study 1 day after it was submitted. “I have to conclude this was not peer reviewed,” she says.
Neither Science nor Nature’s editorial staff would
confirm that the journals reviewed the paper and rejected it in part
because of of ethical concerns. In a statement, a Nature representative said the journal sometimes has papers reviewed by a bioethicist. Science
issued a statement saying it supports recommendations in its earlier
commentary and that while a consensus about germline genome editing is
being developed, the journal “will carefully scrutinize all submissions
for both technical and societal concerns and consult broadly.”
Chen, who uses CRISPR/Cas9 in his own research on microorganisms, and
other scientists in China defend their country's ethical oversight of
the new embryo research. Ethical review procedures in the United States
and in China are very similar and based on the same principles, says
Kehkooi Kee, a stem cell scientist also at Tsinghua, who earned his
advanced degrees in the United States. Kee says that at Tsinghua a
proposal for such work would have to be vetted by the university
hospital's own institutional review board (IRB) as well as by the IRB of
the collaborating hospital that supplies the donated embryos. At the
national level, he says China's funding agencies do check on whether a
grant applicant has the proper ethical approvals. Chen adds that in
light of the current controversy, review boards "will probably be more
strict," he says.
But he’s adamant the newly published research has value even if some
consider its results a failure. Determining if these embryo engineering
techniques can be useful in curing disease can be achieved "only by
doing this kind of research; we might possibly see some positive outcome
resulting from many failures," he says. Kee also defends the work. "The
conclusion is valid, they are not hiding anything, and they are not
saying this technique is ready for use in the clinic," he says.
The China work was funded by national grants and rumors continue to
circulate that several other China teams have done similar embryo work.
In the United States, such experiments could only take place with
nonfederal funding because of a long-standing congressional prohibition
on using federal funding for any research that destroys or puts at risk
human embryos.
Regardless of where scientists stand on this new research, it has
highlighted their shared desire to discuss whether, if ever, gene
editing should be used in human embryos to prevent disease. Doudna is
now helping to organize an international meeting later this year to come
up with guidelines. “I think the goal of that meeting is to come
together and identify a broader consensus about the appropriate way to
proceed with these experiments,” she says. Now that the first human
embryo gene-editing paper has been published, she adds, “we feel some
urgency.”
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