Hype versus reality in human embryo genome editing

Tanya Brigden

17 August 2017

This blog was co-authored by Tanya Brigden and Laura Blackburn

Hype surrounding a recent Nature paper reporting the editing of human embryos by an American team sent many parts of the media into a frenzy, hailing the start of the 'designer baby' era. The researchers used CRISPR-Cas9 gene editing to correct a gene causing an inherited heart condition in embryos created in the lab.

The research follows other efforts from groups in China, and shows that it is possible to carry out accurate genome editing of embryos. However, the findings also highlight many of the challenges remaining and put into perspective the difficulties (if not the impossibility) of editing the genes required to change complex human traits.

Correcting a disease-causing mutation

The research team used eggs from a healthy donor and created embryos by injecting sperm from a male donor affected by an inherited heart condition called hypertrophic cardiomyopathy (HCM), which causes thickening and stiffening of the heart muscle, leading to heart failure in some cases. HCM is also the commonest cause of sudden death in otherwise healthy young adults. Only one copy of a faulty gene causes disease in a patient, and in this case, the researchers used CRISPR-Cas9 gene editing to correct a gene called MYBPC3, which is responsible for around 40% of HCM cases.

They found that the relative timing of the injection of the sperm and editing machinery into the egg affected the success of subsequent embryo editing – when the sperm and CRISPR-Cas9 apparatus were injected at the same time, meaning that editing took place at the point of fertilisation, editing was much more successful. Out of 58 embryos created in this way, 42 were successfully edited, and 50% of these survived for five days post-fertilisation. The researchers also didn't detect any off-target effects, where unintended edits occur in other parts of the genome, and they created only one 'mosaic', where some but not all of the cells in the embryo are successfully edited .

Food for thought

One interesting finding from the research was that the repairs were made using the healthy gene copy provided by the egg, rather than using the template provided by the researchers. This suggests that embryos might have different DNA repair mechanisms from adult cells and is an area for further research. It could mean, for example, that it will be more challenging to correct homozygous embryos – those with two faulty gene copies – if embryos don't use the gene editing template provided and instead revert to gene copies already found in the embryo. At this point, investment in basic research to understand the biology of this process seems more practical and relevant.

Beyond the medical questions, a number of ethical concerns have arisen surrounding the manipulation of the human genome. The results of this study have been accompanied by fears of a ‘slippery slope’ towards editing for enhancement purposes, generating inequality. Whilst the prospect of genome editing for non-medical purposes should be viewed with alarm, ‘designer babies’ is a generally unhelpful and inaccurate term that fails to account for the complexities of engineering desirable human traits. Height, for example, can be influenced by hundreds of genetic variations, as well as environmental factors. The researchers in this instance have repaired a single gene mutation (in this case a deletion) on a single gene - a defect known to cause serious heart disease. Making changes to hundreds of genes controlling complex traits lies far beyond the scope of current technology and scientific understanding.

More realistic moral dilemmas include the ethical implications of making permanent, heritable genomic edits that will affect the individual and any future offspring. Despite the clear benefit of avoiding a heritable genetic disease, some ethicists voice concerns that germline modification could lead to generations of offspring who have not had an opportunity to consent to such interventions. However, even if non-existent beings can be said to have any right to consent to modifications, an issue of debate, parents are frequently permitted to make medical decisions on behalf of their children.

Cause for concern?

More worrying is the fact that we do not yet know what the long term effects of germline gene editing may be. Safety concerns must be prioritised; unintended changes to the genome could result in the development of cancers and other pathologies. Whilst testing techniques such as pre-implantation genetic diagnosis (PGD) involves the destruction of a single (non-vital) cell to assess the genetic status of the embryo, every cell in an edited embryo must be assessed to ensure the absence of mosaicism and off-target effects, destroying the embryo. Before CRISPR could be used on an implantable embryo, we must find another way to detect potentially harmful unintended effects.

CRISPR-Cas9 technology needs to offer new options to couples at risk of having a child with a genetic disease, beyond current treatments such as pre-implantation genetic diagnosis (PGD). For the relatively small number of couples that would not be able to produce unaffected embryos (for example, when both parents carry a homozygous mutation), CRISPR offers an opportunity that would not otherwise be available. But does the potential benefit – for a minority – justify the use of extensive resources, and the significant ethical objections that arise?

The way forward

There is a flip side to ethical arguments against gene editing. Are we not duty bound to investigate potentially safe and effective means of curing genetic disease? Rather than wholeheartedly embracing or rejecting gene editing on the basis of ethical considerations, a middle ground would enable the use of CRISPR technology for therapeutic purposes only, against a backdrop of strict laws and regulation (in the UK, by the HFEA). We already regulate PGD in a similar way to ensure it is only used for medical purposes.

Of course, it is hugely important that this technology is not rushed into use before it can be proven to be safe, and also that a societal consensus is reached regarding which applications should be permitted. Researchers themselves emphasise the need for further investigations to ensure the safety and efficacy of CRISPR. Undoubtedly, we must proceed with caution. However, we should also celebrate this advancement in a field of research that may one day help eradicate many devastating diseases. Public debate on the ethical issues should be encouraged, but we must be careful not to jump to conclusions about an imminent race of super babies. This is not the dawn of a ‘designer baby’ era.

 

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