Genetically modified human embryos reignite ethical debate

Human embryos are at the centre of a debate over the ethics of gene editing.                 CREDIT: Dr. Yorgos Nikas/SPL

Human embryos are at the centre of a debate over the ethics of gene editing. CREDIT: Dr. Yorgos Nikas/SPL

The recent editing the genomes or rather genetically modifying of human embryos has reignited ethical debate.

There have been widespread rumours that such experiments had been conducted, which sparked a high-profile debate last month, about the ethical implications of such work.

Chinese scientists, in the world first, earlier in the week, 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 results are published in the online journal Protein & Cell.

The researchers led by a gene-function researcher at Sun Yat-sen University in Guangzhou, China, Junjiu Huang, 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.

A stem-cell biologist at Harvard Medical School in Boston, Massachusetts, United States, George Daley, told Nature: “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.

“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 Nature in March that because the genetic changes to embryos, known as germline modification, are heritable, they could have an unpredictable effect on future generations.

Also, mothers may one day be able to prevent their children from inheriting mitochondrial defects. Therapies that modify diseased eggs are inching closer to the clinic, but researchers are still hotly debating the safety and ethics of the most promising techniques. These involve combining the nucleus of the mother’s egg with mitochondria from a healthy woman to create a ‘three-parent embryo’.

In the April 23 issue of Cell, one team proposes an alternative: neutralizing the faulty mitochondria. Some researchers say that the approach could help enable the ethically questionable practice of engineering human embryos to have modifications that would be passed on to future generations.

It has been shown that about one in 5,000 people worldwide has a disorder caused by faulty mitochondria, the organelles that supply the cell with energy. In others, the faulty organelles worsen diseases that arise by other means, such as some cancers.

According to the Cell study, roughly 60 to 95 per cent of the mitochondria in a cell must be faulty for disease to develop.

A molecular biologist at the Salk Institute for Biological Studies in La Jolla, California, United States, and an author of the Cell study, Alejandro Ocampo, said: “In most cases, however, just a small fraction of the hundreds of the thousands of mitochondria in an egg carry flaws.”

Meanwhile, 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.

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 cells 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.

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.

Huang said: “If you want to do it in normal embryos, you need to be close to 100 per cent. That is 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 said.
Ethical questions

Huang said 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 added 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 acknowledged 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 maintained 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 said.

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