The Crispr/Cas9 'molecular scissors' technique entails replacing parts of a genome.
After the United Kingdom gave scientists the green light to genetically modify human embryos, it is likely that other countries will follow suit, because this type of genetic therapy could prevent people from developing life-threatening diseases even before they are born.
But scientists have raised flags of caution about the possible dangers of heritable therapy and its implications for the discipline as a whole.
“[This approval] is just for experimental, not therapeutic, purposes,” said Michael Pepper, the director of the Institute for Cellular and Molecular Medicine at the University of Pretoria. In other words, this form of gene editing, known as germline editing, cannot be used on patients.
A number of groups around the world, and in South Africa, are doing gene editing. But those researchers are editing adult human cells, which is known as somatic gene editing. Changes in these genes are confined to the person who receives the treatment and are not passed on to future generations. Examples include editing the human genes for sickle-cell anaemia or haemophilia.
“Somatic cells are your body cells,” Pepper explained. “Germline [cells] are the gametes: the eggs and the sperm.” If an embryo’s germline make-up is edited, this can be passed on to its descendants.
The UK’s Human Fertilisation and Embryology Authority has given permission for a very specific form of germline editing: a team at the Francis Crick Institute, led by Kathy Niakan, will be allowed to edit the germlines in healthy human embryos, using a “molecular scissors” technique known as Crispr/Cas9. Using this technique, researchers are able to target and remove parts of the genome and replace it with preprogrammed bits of replacement genome. The embryos will be destroyed after seven days.
“The knowledge acquired from the research will be important for understanding how a healthy human embryo develops,” the institute said in a statement. “This knowledge may help improve embryo development after in vitro fertilisation and might provide better clinical treatments for infertility, using conventional medical methods.”
Niakan’s research will begin in the next few months, subject to ethics approval.
This is the first time that a regulatory authority has given approval for germline editing on human embryos, but it is not the first time it has been done. Last year, Chinese scientists, led by gene-function scientist Junjiu Huang at Sun Yat-sen University, edited the germline of “nonviable” human embryos – those that would not result in a live birth.
They published their findings in online journal Protein & Cell to an outcry from the scientific community. Huang said that neither Nature nor Science, two of the world’s most respected scientific journals, would publish his findings, in part because of ethical objections.
Both publications have declined to comment.
Chinese scientist Junjiu Huang made waves with his work on nonviable human embryos.
In the paper’s abstract, the authors write that the technique used, Crispr/Cas9, is not precise enough, results in mutations and will require more development before it is used for clinical purposes.
In December last year, the United States, British and Chinese academies of science convened an international summit to chart a way forward on human gene editing. In the summit’s closing statement, they said: “Powerful new techniques … make it possible to perform gene editing – that is, precisely altering genetic sequences – in living cells, including in humans, at much higher accuracy and efficiency than ever before possible.”
A concern about these new techniques is that, though powerful, they are not accurate and, if used on germlines, these changes would be passed on to successive generations.
“A problem is that with all of these techniques there are off-target effects,” Pepper said. If the technique is on target, you alter the gene you intend to change; if it is off target, it affects other genes.
“The tools should have very specific effects, but none of these techniques is 100% failsafe,” he said. “You get effects on genes other than those you wish to alter.”
This is what Huang and his team highlighted in their paper, although other scientists have said that the “untoward mutations” Huang’s team reported were a result of their use of “nonviable” embryos.
Pretoria University’s Michael Pepper says germline editing would only be allowed in South Africa for research purposes. (Madelene Cronjé)
Off-target effects in somatic cells would affect the patient and, because the changes are confined to one individual, the risks of the treatment could be assessed and weighed against the potential benefits.
The human gene editing summit highlighted this: “[Germline changes] will be carried by all the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool … [Problems include] the difficulty of predicting harmful effects that genetics changes may have under the wide range of circumstances experienced by the human population … [and] the fact that, once introduced to the human population, genetic alterations would be difficult to remove and would not remain within any single community or country.”
It was also possible that “permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively”.
The summit initiated a consensus study into human gene editing, with the first fact-finding meeting next week in Washington, DC.
But some scientists are concerned that germline editing could bring the field into disrepute and stall many life-saving therapies. In an opinion piece in Nature last year, biotechnology industry players, led by Edward Lanphier, called for a voluntary moratorium on germline editing.
An artist’s depiction of the Crispr system in action. (Illustration by Stephen Dixon, McGovern Institute for Brain Research)
Lanphier heads up Sangamo BioSciences, a biotechnology company that produces molecular scissors for somatic gene editing.
“There is a fear of the negative impact [human germline editing] could have on important work involving the use of genome editing techniques in somatic [nonreproductive] cells,” the authors wrote.
“Genome editing technologies may offer a powerful approach to treat many human diseases including HIV and Aids, haemophilia, sickle-cell anaemia and several forms of cancer.
“In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations if they affected the germline. This makes it dangerous and ethically unacceptable. Such research could be exploited for nontherapeutic modifications. We are concerned that a public outcry about such an ethical breach could hinder a promising area of therapeutic development.”
They called for awareness campaigns to educate the public about the difference between somatic gene editing and germline gene editing.
Asked whether it was likely that South Africa would see human germ-line editing, Pepper said: “In terms of the legislation, there is some restriction about manipulating gametes [eggs and sperm], but it does not specifically refer to germline editing. That would require ministerial approval. Germline editing for research purposes may be permitted, but for the foreseeable future this would not be allowed for therapeutic purposes.”
But he said it was likely that somatic gene therapies would eventually be practised in South Africa.
“With economies of scale bringing down costs, I’m sure this will become a treatment available to South Africans.”
Decoding scientific jargon explained
Somatic cells: Any cells in the body that are not sperm or egg cells. Somatic gene editing does not get transmitted to future generations.
Germlines: These are sex cells – contained in the sperm and egg – that pass genes on to descendants and, if edited, the changes are transferred to offspring.
Clinical use: The therapy is used on patients. Experimental use: The editing is confined to the laboratory and is not used on patients.
Crispr/Cas9: This is a recently discovered gene editing technique, derived from how bacteria protect themselves against viruses. It allows researchers to replace pieces of genomes. Although it is one of a number of “molecular scissors” methods that are available, it is considered one of the most accurate techniques.