Time for a moratorium on human germline genome editing?

International experts are calling for a ban on nuclear genome editing of the human germ line in clinical practice.

What is genome editing?

Genome editing is a technique for genetic engineering or genetic modification. It uses some form of nuclease enzyme to cut host DNA at a specific location and then allow the incorporation of a synthetic section of DNA to be inserted in the same place using normal cellular mechanisms. There are different types of genome editing that use different nucleases; the recently developed CRISPR/Cas system has generated a lot of excitement thanks to the speed and precision of genome editing it appears to allow.

There are various potential therapeutic applications of genome editing; it holds particular promise as an approach to gene therapy, replacing absent or non-functional genome sections with engineered, healthy replacement sequences to restore function. In theory, it could also be used for the therapeutic modification of human embryos – for example, to prevent a genetically inherited disease from arising.

Any form of germline (heritable) human genetic modification – of embryos or adult reproductive cells - is currently illegal in countries with regulatory systems. However, the greatly enhanced potential of new genome editing techniques are calling this blanket prohibition into question, with experts calling for discussion. A recent US summit of academic experts convened for this very purpose summarised the situation up nicely writing in Science: “The simplicity of the CRISPR-Cas9 system allows any researcher with knowledge of molecular biology to modify genomes, making feasible experiments that were previously difficult or impossible to conduct.” 

Risks, rewards and recommendations

Scientific experts have begun weighing in on this issue; a recent piece in Nature anticipated that reports of human embryo genome editing would shortly be published, and called for an agreement between scientists not to take this further, saying: ‘In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations. This makes it dangerous and ethically unacceptable. Such research could be exploited for non-therapeutic modifications. We are concerned that a public outcry about such an ethical breach could hinder a promising area of therapeutic development, namely making genetic changes that cannot be inherited’.

They also said that ‘there is a fundamental ethical issue in crossing the boundary to modifying the human germ line’. However, others contend that once the safety concerns and public objections are allayed there will be no good reason to sustain such a moratorium. Renowned geneticist George Church told Nature News that it should be in place “until safety issues are cleared up and there is general consensus that it is OK”.

The US summit of experts made four recommendations that steps should be taken to:

1. Strongly discourage germline genome modification for clinical application in humans internationally
2. Create sources of information from ‘experts from the scientific and bioethics communities’ on the risks and rewards of genome editing and associated ethical, social, and legal implications
3. Support transparent research to evaluate the efficacy and specificity of CRISPR-Cas9 genome engineering technology for germline gene therapy
4. Convene a globally representative group of experts in the science, clinical applications, law, bioethics, public, government agencies and interest groups to consider the issues

The International Society for Stem Cell Research (ISSCR) has just released a statement supporting a moratorium on clinical genome editing of human embryos to enable more research into the potential risks and ‘a deeper and more rigorous deliberation on the ethical, legal and societal implications of any attempts at modifying the human germ line’. Some researchers worry that a public backlash could rebound on efforts to develop therapeutic somatic (non-reproductive) cell genome editing

Moving on from mitochondrial replacement

The ISSCR statement is careful to state that it does not represent a position on the clinical testing of mitochondrial replacement therapy – a technique recently legalised in the UK for the first time in the world.  It is interesting to note, however, that mitochondrial replacement is (accurately) referred to as germline modification in the statement.

UK proposals in favour of legal amendments to permit the technique specifically exempted mitochondrial DNA replacement from other forms of human germline modification on the basis that it represents a tiny proportion of the complete human genome and that ‘the impact of mitochondrial DNA is limited to powering the cells of the body and that it does not have any impact on the physical characteristics and personality traits of any resulting child, which come solely from nuclear DNA’.  This being said mutations in that same mitochondrial DNA are sufficient to produce devastating disease, so in some senses the same argument might be made for any very small and well-defined section of the nuclear genome (say, the site of a disease-related mutation), that it does not affect physical characteristics of personality traits other than the disease-related function in question. Hence the UK moves are not irrelevant to the genome editing debate.

Science is really only starting to reveal just how great the complexity of human genome regulation is. Until more is known about the interactions between different areas of the genome, the true impact of induced changes in one area on others cannot be reliably predicted. But science moves quickly, so researchers are right to flag up the need for much wider and more public (as well as expert) discussion of the issues around human germline genome editing.