Is it possible to eliminate disease-causing mutations from the human genome?
In a study reported in the journal Protein & Cell, researchers from China have used genetic editing to correct disease-causing mutations in cloned human embryos.
The investigators used a procedure known as base editing to repair mutations in the HBB gene that give rise to beta thalassemia.
Beta thalassemia is an inheritable blood disorder. It causes potentially life-threatening anemia in people who carry two copies of the mutated HBB gene.
“Our study demonstrated the feasibility of correcting pathogenic mutation by base editing in human cells and embryos,” Puping Liang, PhD, the first author of the study, told Healthline.
While more research is needed on the efficiency, safety, and precision of base editing in human embryos, the investigators believe it holds promise for curing genetic diseases.
“Germline gene therapy by base editor still needs to be investigated and discussed thoroughly,” Liang said. “But clinical applications of somatic cell gene therapy by base editors might be available in the near future.”
Base editing is precise and efficient
This study is the first to use base editing to correct disease-causing mutations in human embryos.
Base editing was pioneered by David Liu, PhD, professor of chemistry and chemical biology at Harvard University.
Also known as “chemical surgery,” base editing uses an RNA-protein complex to catalyze conversions in the nucleotides that make up human genes.
This process allows scientists to target and change specific nucleotides in mutated genes with more precision than CRISPR-Cas9, an older genetic editing technique.
“For some applications, traditional CRISPR nuclease is a preferred approach,” Liu told Healthline.
“But many human genetic diseases are caused by single point mutations that need to be precisely corrected, rather than disrupted, in order to treat or study the corresponding disease,” he continued.
Beta thalassemia is one of those diseases.
In earlier studies, Liang and other Chinese researchers tried to correct HBB mutations using CRISPR-Cas9 and another technique known as homology directed repair.
Compared to those earlier efforts, base editing proved to be more precise.
“The researchers observed quite efficient correction of the target mutation, by in vivo genome editing standards,” Liu said.
Ongoing technical advancements might help further improve efficiency in base editing.
For example, Liu’s team at Harvard has recently developed fourth-generation base editors. They show improved editing efficiency and product purity.
“We are hopeful that base editing might advance the study and treatment of genetic diseases, and our laboratory is working hard toward this goal,” he said.
Ethical concerns remain
None of the edited embryos in Liang’s study were implanted in utero or allowed to develop into fetuses.
But the changes made to the mutated HBB genes are heritable.
In other words, they could theoretically be passed from parent to child.
This possibility has raised concerns among bioethicists, scientists, and policymakers.
“There has been a long-standing debate in bioethics and the public forum about the idea of making permanent or heritable changes to the genome of individuals,” Josephine Johnston, director of research at the Hastings Center, a bioethics research institute, told Healthline.
“There are a lot of broadly writ safety concerns that are heightened by the idea that the change would be heritable. Because how do you assess intergenerational safety? It’s very difficult to know how you actually design those studies and whether it’s ethical to do that,” she continued.
“There are also concerns that some people have about whether or not it’s the appropriate role for humans to play in human evolution,” she added.
Some stakeholders have taken the position that heritable human genome editing should be avoided entirely.
Others have argued that it might be ethically permissible to use heritable human genome editing to prevent or treat serious genetic diseases.
Earlier this spring, the National Academies of Sciences, Engineering, and Medicine released a report on the subject.
It took the position that clinical trials for genome editing of the human germline “could be permitted in the future, but only for serious conditions under stringent oversight.”
For now, however, federal regulations limit this field of research in the United States.
“In the U.S., if you are going to develop this [procedure] in order to offer it to patients, you would need to go to the [U.S. Food and Drug Administration] with your study. And the FDA is currently prohibited from considering any application that involves germline or heritable modification,” Johnston said.
“It’s not exactly illegal, but you could not do human clinical trials of this,” she continued.
Liang thinks that more research and discussion are needed to address ethical concerns about base editing in human embryos.
“From the view of technology, the safety issues associated with gene editing may be solved one day in the future,” he said.
“As to the ethics issues, the public, the scientists, the bioethicists, and the governments should reach a consensus on when it is ethical to modify the human germline.”