A lackluster first attempt suggests we're a long way off from safely gene-editing human babies.
Three-day old human embryo. Image: RWJMS IVF Program/Wikimedia
A group of Chinese researchers has declared that they've taken a step forward in transcending nature's constraints on humans.
Scientists from Sun Yat-sen University in Guangdong, China announced this week that they attempted to modify a disease-causing gene in human embryos using a controversial new gene-editing technique called CRISPR-Cas9.
Their study, published in the online journal Protein & Cell, marks the first time scientists have reported tampering with the genetic material of human embryos.
CRISPR-Cas9 uses an enzyme system from bacteria that can recognize and splice DNA at highly targeted locations. Its use in reproductive human cells is controversial because scientists don't yet know what type of effects it might have. Though the Sun Yat-sen researchers specifically used non-viable embryos in their experiment, experts are concerned that the study makes advances towards genetically engineering viable embryos—a process that could cause unintended, harmful mutations in recipient babies and their future offspring.
Many researchers had publicly expressed concerns in anticipation of the Sun Yat-sen study, which has been rumored to come out for a couple months. Last month, before any such research had been published, two independent teams of scientists published editorials in Nature and Science calling for a pause on the use of CRISPR-Cas9 in human reproductive cells.
"We have a lot to understand about how this technology works in reproductive cells, such as how safe it is, how efficient it is, and what level of off-targeting occurs," Jennifer Doudna, a researcher at the University of California, Berkeley who helped invent CRISPR-Cas9, told Motherboard last week, before the Sun Yat-sen study came out. (Off-targeting refers to when CRISPR-Cas9 enzymes miss the gene they are targeting.)
The editorials clearly did not stop the Sun Yat-sen scientists, led by Puping Liang, Yanwen Xu, Xiya Zhang and Chenhui Ding, from publishing their results. In their experiment, they targeted a specific gene called HBB, which is known to cause a life-threatening blood disorder called β-thalassaemia. Their efforts were met with limited success. Less than 13 percent of the embryos that the scientists treated with CRISPR-Cas9 actually showed evidence of the intended gene-editing.
"Our study underscores the challenges facing clinical applications of CRISPR-Cas9," the authors concluded in their study, saying that further investigation is "sorely needed."
Of the 54 embryos that the Sun Yat-sen scientists treated with CRISPR-Cas9 and tested, only 28 were spliced and a mere seven showed signs of successful editing.
"This is a rather inauspicious start."
The low success rate suggests that CRISPR-Cas9 is not anywhere near ready for primetime in human embryos, according to Arthur Caplan, head of medical ethics at New York University's Langone Medical Center.
"This is a rather inauspicious start," said Caplan. "The technique didn't cleave where the scientists wanted, they got crossovers they didn't expect—I'd say the experiment didn't work very well."
Caplan believes the international scientific community needs to weigh in on the ethics of the experiment. He is concerned that public blowback to the Sun Yat-sen study might lead to policies that slow down important research on genetic engineering as a whole. Many experts, for instance, believe that current research should be focused on animal models, he said.
"People will be uncomfortable with research on human embryos," said Caplan. "You won't get that kind of pushback from studying animal embryos."
In their paper the researchers emphasized that, due to ethical concerns, they only used non-viable embryos with one egg and two sperm nuclei. They reportedly obtained the embryos, originally created for in vitro fertilization, from consenting patients at local fertility clinics.
According to the scientists, their study adhered to the ethical standards outlined in the World Medical Association's Declaration of Helsinki. They also stated that they received approval from Sun Yat-sen University's Medical Ethics Committee.
Protein & Cell is a peer-reviewed, open-access journal launched by Chinese scientists in 2010. "It's not a top-tiered journal," said Caplan, who told Motherboard that the paper from Liang and colleagues read more like a case report than a rigorous study to him.
Other experts are more qualified in their criticisms of the new study. The scientists made a case for using non-viable embryos that are otherwise discarded in fertility clinics, said George Church, a geneticist at Harvard University.
For instance, the Chinese researchers cite previous studies indicating that embryonic cells might have lower off-targeting rates than cancer cells, which are often used for CRISPR-Cas9 research, said Church. He points out that using non-viable embryos could help scientists more accurately assess the safety and efficacy of gene-editing techniques without endangering clinically viable embryos.
That said, the scientists did not use the best available techniques for their experiment, according to Church. "There are improvements in the Cas9 technology that greatly reduce off-target mutations that Liang et al cited but did not employ," he said. "While it would be nice if they had tried the best technology, the results are still quite relevant."
Many experts believe that current research should be focused on animal models
The technological improvements that Church cites are logical next steps in gene-editing experiments on human embryos. But it's unclear, given how strongly many Western scientists have advised caution, what form this research will take moving forward. It's rumored that at least four groups in China are currently researching gene-editing in human embryos.
Caplan believes that the Sun Yat-sen study won't compel too many leading scientists to seriously hop on the research—if anything, it sounds a warning that we're not quite there yet. "I don't think the world, ethically, will be different tomorrow due to this one report," he said. "The results just aren't strong enough."