Page URL:

Biomedical Research and Human Applications

This policy document is the second part of a response submitted by the Progress Educational Trust (PET) to a Call for Evidence (.pdf 228KB) issued by the Nuffield Council on Bioethics, as part of the latter's project Genome Editing.

What is the current state of the art in the field? what are the current technical limitations and constraints/bottlenecks?
Many of the technical limitations that previously restricted genome editing have been lifted by the advent of CRISPR, with its improvements in accuracy and efficiency.
A challenge that remains is the problem of accidental rather than intended modifications to DNA. These 'effects' or 'events' can be 'off-target' (occurring in parts of the sequence that that were not targeted with an intended modification), and can also be 'on-target' (occurring in parts of the sequence that that were targeted).
Looking for these accidental modifications is no simple matter - it involves sequencing whole genomes before and after genome editing has taken place, in order to make comparisons. Then there is the added challenge of distinguishing these accidental modifications from discrepancies between genomes due to naturally occurring somatic mutations (mutations whose frequency in our cells increases as we age).
Whether the aim is to edit the genomes of many cells, or whether the aim is to edit the genome of one cell or a few cells (a gamete or embryo) which will in turn give rise to many cells, there is the challenge of mosaicism - unintended genetic variation between cells. Where genome editing experiments are carried out on human embryos, mosaicism is less likely if the genome is edited at an earlier stage of embryo development.
The upshot of this is that while it is useful to carry out research on nonviable embryos donated by fertility patients - for example, the pioneering Chinese research which used CRISPR on human embryos in 2015, see - it will be even more useful, in the longer term, to create human embryos specifically for research and subsequent destruction. Indeed, as the Hinxton Group argues in its Consensus Statement on Genome Editing Technologies and Human Germline Genetic Modification (.pdf 136KB), doing this will be necessary if experiments in this area are to make progress.
Efforts to detect and minimise accidental modifications and mosaicism, and understand the consequences of these phenomena, are important and ongoing.

What are the main directions of travel? what are the envisaged endpoints/applications?
The main directions of travel in biomedical and human applications of genome editing are research improving our understanding of human biology (including genetic disease), the development of somatic cell therapies, and - looking further ahead, and provided that various conditions are satisfied - increasing the reproductive options available to people (including carriers of genetic disease) who wish to give birth to a healthy child.
Looking even further ahead, if we are ever in a position to derive gametes in vitro (creating viable human germ cells by inducing pluripotency in somatic cells), then genome editing tools could also play an important part in that process. However, this is still a distant prospect, legally as well as scientifically. A change in law would be required in the UK before it was permissible to use in vitro derived gametes in treatment, regardless of whether or not genome editing was involved.

What are the main 'drivers' and 'obstacles' in relation to envisaged endpoints?
Commercial interests are important in driving developments in genome editing. A report by the market research company Markets and Markets estimates that the genome editing industry will be worth $3.5 billion by 2019. This industrial growth will help expedite the achievement of envisaged endpoints, but also underlines the importance of policymakers, regulators and non-commercial actors exerting some influence in the field.
The CRISPR approach to genome editing is currently the subject of a high-profile intellectual property dispute in the USA, the resolution of which has the potential either to impede or to assist in the development of genome editing. Whether advances in genome editing are on balance helped or hindered depends on how long it takes for the dispute to be resolved, and how the prevailing patent holders choose to use and enforce their patent rights.

What bearing do international ethical debates and agreements (eg, high level statements or calls for moratoria) have on the pace or organisation of research?
International ethical debates and agreements have a significant impact on research. Overly restrictive or insufficiently clear regulation, or the prospect of such, can act as a serious disincentive to public and private funding.
One of the most important challenges in debates and agreements concerning genome editing is to retain a clear sense of the distinctions between the many different possible applications of this technology, so that these applications can be given specific and separate consideration. It should be possible for national and international institutions to calibrate their approach to genome editing, so that some applications of the technology are approved even if others are not, and so that basic research can proceed.
It is also important for debates and agreements to take account of developments as they unfold, in what can be a very fast-moving area. As the Hinxton Group argues in its Consensus Statement on Genome Editing Technologies and Human Germline Genetic Modification, 'policies governing science nationally and internationally ought to be flexible, so as to accommodate the rapidity of scientific advance as well as changes of social values'.
Moratoria are profoundly unhelpful in relation to genome editing. They are unnecessary in well-regulated jurisdictions, they are ineffective in poorly regulated jurisdictions, and they are liable to be blunter and less granular than de jure regulation with the result that diverse applications of genome editing are all tarred with the same brush.
Unless the terms of a moratorium include clear deadlines and mechanisms for review, then a moratorium amounts to an indefinite and disingenuous ban. In the absence of clear sanctions for breaching the terms of the moratorium, the harshest consequence for such a breach is liable to be the prospect of bad publicity - a prospect that brasher organisations will take in their stride, allowing them to steal a march on more scrupulous organisations who will find themselves struggling for approval and funding. The net result of a moratorium is likely to be apprehension and confusion, when what is really required in this area is confidence and clarity.
As our director Sarah Norcross argues in her article 'Genome editing raises complex issues - banning it is not the answer' in the Observer: 'We think a debate about any new scientific advance is informed and enriched by continued research to understand and refine these techniques in a laboratory, under strict regulatory limits and scientific scrutiny. Many of the questions that the public and policymakers will rightly raise can be answered only if researchers are actively investigating the techniques, testing a variety of hypotheses and advancing their own knowledge. A moratorium on research would be a moratorium on this understanding.'

Who should lead and who should be involved in setting policy for research and human applications of genome editing? is this significantly different from other kinds of experimental or reproductive medicine?
The protagonists of genome editing - the researchers, policymakers, regulators and critics - are not substantially different from the protagonists of any other area of experimental or reproductive medicine. We do not believe there is a need to establish a new policy or regulatory body to lead on this subject in the UK at the present time.
Of course, it is vital for the general public to be involved in discussion of any experimental or reproductive medicine that breaks new ground and stands to have a major impact on society. This is certainly the case in relation to genome editing.
As well as the lay public learning from experts, we must also remember that the lay public is more than capable of coming up with useful and counterintuitive ideas that make experts see biotechnology with fresh eyes. Our own charity specialises in organising public events where experts and laypeople learn from one another, and we can testify to the fact that this approach is invaluable.
Even the most outlandish suggestions and thought experiments by ethicists, philosophers, science fiction authors and members of the public have a role to play, in ensuring that we think in an open-ended way about groundbreaking technologies such as genome editing. That said, we must always take great care to distinguish between fact and fiction, and to distinguish between what is currently or imminently possible and what is more speculative.

What are the significant decisions that need to be taken before therapeutic use of genome editing may be contemplated (for non-heritable and heritable genetic changes) and who should have the responsibility for those decisions?
The distinction between somatic and germline therapy is especially important here. Genome editing is already having a significant impact on somatic gene therapy, a field that that has existed for decades but has faced formidable challenges and setbacks, meaning that it has been slow to move beyond the experimental phase.
Genome editing provides a means to circumvent some of these obstacles and has already yielded some remarkable results, such as the use of TALENs to reverse advanced leukaemia in one-year-old British baby Layla Richards in 2015. Such experimental therapies are subject to well-established standards of safety, ethical scrutiny and clinical judgement, and are legally permitted in the UK if they meet these standards.
The use of genome editing in germline therapy, by contrast, would not be possible in the UK without a change in the law. And for good reason.
The Nuffield Council on Bioethics argued persuasively in its report Novel Techniques for the Prevention of Mitochondrial DNA Disorders: An Ethical Review (.pdf 1.13MB) that mitochondrial donation techniques used in treatment should be regarded as germline therapies. Following the passing of the Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 by Parliament, two such therapies can now legally be used in the UK, if a licence is granted by the Human Fertilisation and Embryology Authority (HFEA). The reason these germline therapies are currently permitted, while other germline therapies would not be permitted, is not because the law is capricious but rather is because of an important distinction.
Mitochondrial donation is a special case where the germline is changed by moving DNA molecules from one place to another without changing the gene sequence within these molecules. Genome editing, by contrast, does involve changes to the gene sequence, thereby offering different possibilities and involving different risks. It is reasonable that if there is case for permitting germline genome editing in therapy, then this case needs to be made anew and the law changed accordingly.
Parliament is responsible for deciding whether or not to change the law. Before it can do so, it will need to be satisfied that the relevant genome editing techniques are safe and efficacious (to the extent that this can be established in non-human models and early embryos), and it will need to consider the specific use(s) to which the techniques might be put. Crucially, the public's opinion on the matter will need to be sought and assessed.
The past decade of UK deliberation on the subject of mitochondrial donation has involved a flexible yet robust strategy, which has allowed scientists and policymakers to keep abreast of one another. Lessons learned from this experience will be useful when it comes to genome editing and the law.

Are the benefits and costs of treatments that involve genome editing likely to be distributed equitably (or any more or less equitably than existing or alternative treatments)? In what way might genome editing differentially affect the interests of people in vulnerable or marginalised groups?
It is difficult to answer this question in the abstract, as the answer would depend very much on the specific treatment. In the UK, the answer would also depend on whether and how the NHS commissioned the treatment - central commissioning by the NHS is very different from local commissioning by CCGs, with the latter liable to result in inequity.
Speaking more generally, it is usually a safe bet that the affluent will be able to avail themselves - to a greater or lesser extent - of treatments that others will find more difficult to access. This is true of all medicine, and is perhaps especially true of reproductive medicine.
If whole genome sequencing becomes more routine, then subclinical or ambiguously pathogenic gene variants may come to light via sequencing, which might never have affected a person's health. Some may seek to improve their health - or, regulation permitting, the health of their offspring - by modifying the relevant genes with genome editing. Some may be able to afford to do this, while others may not.
This hypothetical scenario poses some challenges, but it is not entirely new. As with all of health, treatments of questionable value may be offered alongside treatments that are of obvious value (to the extent that this is possible within the terms of regulation), and the former may be commercially driven and may promote or exploit unnecessary anxiety. Education and public engagement, to put risks and benefits in context and to encourage enlightened scepticism, will be important to mitigate this.
Some have expressed concern that the vulnerable or marginalised will experience greater stigma and discrimination as a consequence of genome editing. This is a form of the expressivist objection to reproductive choices - as we have explained above, we do not think this objection is well-founded. Nor do we agree with fears that genome editing will bring about a resurgence of eugenic thinking.
Eugenics, when it pervaded mainstream thought in the nineteenth and early twentieth centuries, was predicated on the belief that people were divisible into racial types - some of which were considered superior, while others were supposedly subhuman. This belief has been thoroughly discredited, both scientifically (by advances in our understanding of genetics) and politically.
Eugenics involved a singular mythical ideal of human inheritance and perfection, manifest in the concept of race and in the idea of perfect or perfectible (eu)genes. Eugenicists also argued for coercive means of achieving this mythical ideal.
There is currently no widespread belief in or appetite for such a singular idea of human perfectibility on racial or other such spurious grounds, and there is no credible suggestion that people should be coerced into particular reproductive outcomes. Furthermore, our understanding of genes is now far more sophisticated.
In short, genome editing will not revive a eugenic outlook.