As the battle for ownership to the intellectual property behind CRISPR/Cas9 carries on, the gene editing technology continues to grow at an accelerated pace. However, surrounding the extraordinary research potential of this system is a controversial debate over the ethics of gene editing and genome engineering in humans. In this light, following a January meeting in Napa, California, several scientists co-authored a perspective paper in Science calling for a global moratorium on all human germline modification research until a responsible use of the technology, if any, can be identified. But just four weeks after its online release (and two weeks following its print), the first documented research on human embryonic gene modification was published in Protein & Cell in April 2015, thus igniting a great public debate that has the scientific community split.
The debate centers on the work led by Junjiu Huang, a gene function researcher at Sun Yat-sen University in Guangzhou, China, whose team utilized the CRISPR/Cas9 system to edit the genome of human embryos—a global first, despite previous applications in human adult cells and animal embryos. In Huang’s study, non-viable embryos – intentionally fertilized by two sperms so that they could not result in live birth – were injected with the CRISPR/Cas9 enzyme complex programmed to target and edit the haemoglobin beta (HBB) gene that encodes the human beta-globin protein. Mutations at this gene are responsible for beta-thalassaemia, a potentially fatal blood disorder.
In theory, this genetic modification could provide a promising avenue towards preventing the disease if applied to embryos bearing the mutation. However, the study was predominantly unsuccessful and underscored the serious obstacles to using the technique in medical applications. Of the 86 embryos injected, 71 survived, and just 28 of the 54 embryos tested were successfully spliced. Of these, only four embryos carried the desired genetic change, indicating a success rate of fewer than 5%. Furthermore, Huang’s team found that the edited embryos had a large number of unintended, ‘off-target’ mutations that could be harmful, demonstrating one of the main safety concerns surrounding germline gene editing. The researchers are united in their belief that the technology is not yet ready for any clinical applications; but where the scientific community is split is on the value of basic research that involves genetically editing human embryos.
According to Huang, Nature and Science rejected the paper citing ethical objections (the journals have not yet commented on the claim). This reflects the opinion held by many that Huang’s group crossed an ethical line. Several researchers argue that genome editing in human embryos is dangerous and ethically unacceptable, as it could have unpredictable and heritable effects on the future generation. Edward Lanphier, chairman of the Alliance for Regenerative Medicine in Washington DC and president of Sangamo BioSciences in Richmond, California, asserts that the field and its accompanying technology is too immature to explore human germline-modification research. He believes that the low efficiencies and high numbers of off-site mutations in Huang’s data underlines this concern, and that all research of the sort should be suspended. Lanphier is not alone. Marcy Darnovsky, executive director of the non-profit Centre for Genetics and Society in Berkeley, California, also called for a halt on all human germline-modification experiments. “No researcher has the moral warrant to flout the globally widespread policy agreement against altering the human germline,” Darnovsky said in a press statement calling for improving global policies on human germline modification. “We need to act immediately to strengthen the agreements that put human germline modification off limits.”
However, those in support of Huang’s work argue that a moratorium on research is unjustified. John Harris, a bioethicist at the University of Manchester, UK, says that although the poor performance of Huang’s study “should be a stern warning to any practitioner who thinks the technology is ready for testing to eradicate disease genes,” he believes Huang’s use of non-viable embryos is “no worse than what happens in in vitro fertilization all the time” and avoids ethical concerns. He told Science that he would defend the fundamental scientific value of research into gene editing in human embryos as a means to explore the risks of any potential clinical use. Dusko Ilic, a stem cell researcher at King’s College, London, also agrees that the work done was not unethical, and believes there should be no ethical objections on the matter. George Daley, a stem cell biologist at Harvard Medical School, believes that the study of gene editing in human embryos, eggs, and sperm provides an avenue to answering plenty of basic scientific questions unrelated to any contentious clinical applications, and supports the continuance of such studies solely for the purpose of research.
In 2014, Motoko Araki and Tetsuya Ishii from Hokkaido University, Japan, surveyed 39 countries to examine the international regulatory landscape concerning germline gene modification and found that 29 countries ban the practice. However, an important distinction was made between legal bans and guidelines. Whereas 25 of the 29 countries prohibited germline gene modification by legislation, four countries, including China, forbid the practice by less enforceable guidelines that were subjective to amendment. The fact that the first published research on human embryonic gene modification comes from a country with an apparent ban on such research is surprising – and points to the concerns raised by scientists such as Lanphier and Darnovsky against the study.
Notably, most of these laws were written prior to the emergence of the technology that makes germline editing possible in laboratories around the world. The increasing availability and advancement of the technology raises fresh questions on the debate. Should the increased accessibility require enforcement of more stringent laws that deter any further studies on human embryonic modification, or does this call for a review of the current restrictions in order to encourage this area of study under careful supervision? Considering the complexity of the regulatory environment and the arguments put forth by scientists from both communities, Hank Greely, a bioethicist at Stanford University, has every reason to believe that “a consensus is probably too much to hope for.”