12 October 2020

Research Fellow in Biomedical Ethics, University of Melbourne/Murdoch Children's Research Institute

The transformative impact of CRISPR/Cas9 genome editing was recognised last week, with the Nobel Prize being awarded to its founders Jennifer Doudna and Emmanuelle Charpentier.

Since the prize winners first described this new approach to editing DNA, CRISPR has been used for hundreds of applications in biological research, agriculture, conservation biology and somatic medicine. However, its most controversial use has been in human reproduction, a practice called heritable genome editing (HGE). In 2018 Dr He Jiankui, an associate professor at the Southern University of Science and Technology in China announced he had used CRISPR to edit the CCR5 gene in embryos, resulting in twins who had already been born (see BioNews 997). The goal was to make the children resistant to infection from HIV.

Dr He Jiankui's announcement shocked the world and was condemned as a great violation of research ethics. In response, the US National Academy of Medicine, the US National Academy of Sciences, and the UK's Royal Society formed an 'International Commission on the Clinical Use of Human Germline Genome Editing' with the goal of 'defining a responsible pathway for clinical use of human HGE (HHGE), should a decision be made by any nation to permit its use' (see BioNews 1000). The outputs are a list of 11 recommendations that states should follow should they wish to implement HGE.

The strength of the report is the great detail it gives about the technical progress that has been made with genome editing technologies, their current limitations, and the hurdles such technologies should meet before we proceed to clinical applications. The report makes important general points like the need to engage with diverse communities likely to be affected by HGE.

However, in this article, I wish to discuss two reasons to be critical of the report. One concerns its framing and general relevance. The other is the way it categorises different possible future applications of HGE.

Framing and relevance

A convincing need for a clinical pathway for HGE is not provided in the Commission's report. The actions of Dr Jiankui, which were its catalyst, did not challenge our traditional clinical pathways. Dr Jiankui was a rogue actor, who took steps to hide what he was doing from others. His actions were incompatible with basic research ethics principles and existing guidelines for germline genome editing. If the goal is to prevent repeat actors like Dr Jiankui, we need to focus on compliance with existing standards rather than developing new ones.

Furthermore, if a specific clinical pathway for HGE is warranted, it's not clear why you would attempt to define one now. We are still far from having enough evidence to establish the safety of HGE. This will likely remain the case for some time, given restrictions on research in many places. Furthermore, HGE remains illegal in many parts of the world, including the USA, Europe, and the UK. No countries have announced intentions to relax laws and allow HGE, and China has recently passed legislation to restrict it. While the Commission's report is useful for suggesting some safety hurdles that must be cleared (for example recommendations five and six), the fact that we are so far from doing so raises questions about the need for further recommendations. Why not wait until we have safe technologies that some countries are considering implementing before devising detailed clinical pathways? As knowledge of the opportunities and risks posed by HGE increases, a pathway that is currently appropriate for HGE may well be obsolete in the future.

Categorising different applications

To further the above criticism, consider the six categories of HGE applications the Commission's report distinguishes:

A: Cases in which all of the prospective parents' children would inherit the disease-causing genotype for a serious monogenic disease (defined in this report as a monogenic disease that causes severe morbidity or premature death).

B: Cases in which some but not all of the prospective parents' children would inherit the pathogenic genotype for a serious monogenic disease.

C: Cases involving other monogenic conditions with less serious impact.

D: Cases involving polygenic diseases.

E: Cases involving other applications of HGE, including changes that would enhance or introduce new traits or attempt to eliminate certain diseases from the human population.

F: The special circumstance of monogenic conditions that cause infertility.

The Commission considers that only applications in Category A and some in Category B qualify for a clinical pathway. It's no doubt true that the most likely and logical initial application for HGE will be to prevent a serious monogenic disease, in cases where there are no other options. However, it's not clear whether other applications might become more compelling in the future, or indeed if there is a need to draw distinctions like this at all.

Consider how the report deals with applications to prevent infectious disease: a timely application considering we are currently experiencing a pandemic. Applications of HGE which gives individuals resistance to infectious disease are placed in Category E the same category as genes which enhance normal traits like intelligence. We are told a responsible clinical pathway cannot be defined for this application. But consider the following hypothetical case:

A new infectious disease Cebola has become endemic in some parts of the world, and no vaccine is available. Many die of Cebola in childhood. By altering one base-pair, it is possible to make children immune to Cebola. Base editing technologies are developed which can make these changes precisely, with no other changes made in the genome. It is possible to make individuals immune to Cebola by editing embryos used in IVF or editing men's spermatogonial stem cells.

Although such an application of HGE is unlikely, who knows what the world will be like by the time HGE is safe. The fact that this application is classed by the Commission's report in the same category as one which enhances intelligence is problematic, in my view. What is important is whether an application is safe and is expected to do good and prevent harm it doesn't matter ethically whether the harm would have been caused by an inherited disease or an infectious disease. What I think this shows is the need to assess HGE on an application by application basis, and not draw arbitrary distinctions far ahead of time.

Too many reports?

The Commission's report is the latest of dozens into genome editing and will be followed by another by the World Health Organisation soon. What often gets overlooked in these reports is the existing barriers to basic research into genome editing in germ cells, which is illegal or unfeasible in many parts of the world. If our goal is to use HGE to prevent the death and harm caused by genetic disease, we should be focusing on defining pathways that make responsible research easier around the world, rather than prematurely describing clinical pathways.

Read more:
A pathway to nowhere? A critique of the National Academy of Sciences report on genome editing - BioNews