10 September 2020
On Thursday 3 September 2020, The International Commission on the Clinical Use of Human Germline Genome Editing published its long awaited report. It was tasked with addressing the scientific considerations of human gene editing. It sets out a framework for scientists, clinicians, and regulatory authorities and states to consider when assessing potential clinical applications of human heritable genome editing (‘HHGE’). This comes nearly two years after news broke of the world’s first gene-edited babies in China in November 2018. It intensifies the debate around the use and regulation of human gene editing technology. It comes ahead of a further report by the World Health Organization (‘the WHO’) Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing later this year. The WHO are currently evaluating ethical, societal and legal issues associated with human gene editing (both heritable and non-heritable) and making recommendations on governance mechanisms at both a national and global level to deter and prevent irresponsible and unacceptable use of this technology.
Whilst last Thursday’s report provides a helpful starting point to assist the future management of this powerful evolving technology, it is however straightjacketed by a traditional healthcare and fertility paradigm. Despite its detailed analysis which spans over 200 pages and its proposed framework, the report does not adequately evaluate the scientific considerations or take into account the risks that individuals, organisations and states will not sign up to it, or that they will simply pay lip service to it and undertake HHGE and allied technologies covertly away from public scrutiny or hide in plain sight on their own wider terms. Surprisingly, it does not address any sanctions for non-cooperation or non-compliance with the proposed framework for use of this rapidly developing technology. Furthermore, the International Commission’s report represents a missed opportunity to expand and shift its paradigm and assess human gene editing technology (heritable and non-heritable) in an integrated context that takes wider account of the ongoing rapidly evolving digital, artificial intelligence, genomic, science, epigenetic and human reproductive revolutions.
Background
I first addressed the issue of human gene editing at a Public Policy Projects (PPP) event at the Law Society in London on 9 April 2019 where Professor Lord Robert Winston gave a key note speech entitled “The future of fertility policy in the context of the genomics revolution”. He spoke about the efficacy of IVF treatment and the increasingly important science and practice surrounding the human genome in maximising successful outcomes for fertility patients. I highlighted that rapid changes in medicine, science, genomics and technology continued to challenge and outpace law, policy and regulation. I called for a root and branch overhaul of law and policy to ensure it is fit for purpose. I explained that this was needed to encompass fundamental developments in the advancement and delivery of medicine, science and technology globally. I explained that the landscape in the 21st century is now very different and that this requires a quantum shift in thinking and an enlightened and cohesive approach to legislation. I added that there remained a responsibility for law and policy makers to take proactive measures to regulate this fast-moving innovation and its very significant future legacy.
In June 2019, I wrote two articles entitled “Power, Wealth, Baby-Making and Genetic Policy Responsibilities” and “Global Genetic Policy Responsibilities and Assisted Reproduction” which addressed US law and policy on human gene editing. These articles coincided with law and policy makers revaluating the liberalisation and the future of genetic policy and practice in the US and I called for more consideration, debate and the creation of a new legal framework.
I then published an article with proposals for fertility and wider law reform in the UK in the July/August 2019 edition of Resolution’s The Review Magazine. I explained that the time had come for a new centralised approach to law and policy for the fertility sector in the UK, saying that the establishment of a dedicated Minister for Fertility would help develop a unified voice, agenda and future direction for the fertility sector as a whole. I explained that this would help formulate a mandate for a robust fertility policy and political strategy that encompasses fertility preservation and maximisation, fertility treatment and conception, pregnancy and birth, family expansion and legacy. I went on to say that individual fertility and family building are key components in the stability and future success of our society. I highlighted that the nature of family life, people’s expectations and choices and advances in science and technology have changed significantly over the last twenty years and continue to outpace law and policy frameworks in the UK. As a result, I explained that a paradigm shift in thinking and approach is needed, together with intelligent root and branch law and policy reform. This would require an enlightened and multi-disciplinary approach that encompassed greater understanding and debate about the role and value of digital technology, genomic science and medicine and individual fertility. It would also require a new centralised approach and joined up thinking with healthcare, social welfare, education, science, technology and economic policy.
Subsequently, I went on to deliver a lecture at the LaingBuisson Fertility Forum in London on 1 November 2019 entitled “The future legal and regulatory landscape for fertility treatment: A paradigm shift”. This set out the context for, and a framework governing, a new future genetic and fertility treatment model at fertility clinics. I explained that this new approach would integrate genomic science and medicine into the traditional fertility treatment process including: genomic sequencing of personal genomes, genetic counselling (separate and in addition to psychological and legal counselling) and genetic medicine which could encompass genetic screening or editing of embryos or stem cell gamete creation in future.
This was closely followed by my comment piece in Bionews on 25 November 2019 entitled “Why we need root and branch fertility law reform” and my accompanying detailed discussion paper “Why we need fertility law reform: the paradigm shift”. I then published two subsequent discussion papers “Why we need fertility and wider law reform part II” on 15 January 2020 and “Why we need fertility and wider law reform part III” on 17 July 2020. In these discussion papers, I set out that advances in human gene editing technology has the potential to alter human evolution and revolutionise the human condition, explaining that it is immensely powerful technology which blurs the lines between the physical, digital and biological spheres. Its transformational impact has the ability to be both life changing and life creating. However, in cutting across a wide range of sectors including assisted reproductive technology (ART), science, digital and artificial intelligence, national security, economics, health and social care it creates very significant repercussions, legal issues and policy opportunities. This is why we need enlightened and integrated fertility and wider law reform at a national and international level.
To address this rapidly evolving landscape (intensified by the continuing Covid-19 pandemic) I therefore called in my paper on 17 July 2020 for a top level multi-disciplinary strategy group that operates on a continuous basis in the UK and not just during emergencies. It would comprise bright, forward-looking and strategic thinkers who sit outside the elected political elite and are unconstrained by party politics. They would shift paradigms and deliver enlightened assessments to inform law and policy-makers and shape the future more quickly and effectively. This top level strategy group’s remit would extend beyond that of the government’s Scientific Advisory Group for Emergencies (Sage). It would be tasked with driving innovation, identifying and mitigating risk with joined up thinking between the fertility, technology, science, healthcare, education, economic and other sectors in the UK. It would help respond effectively to the rapidly evolving inter-connected digital, artificial intelligence, genomic, epigenetic and reproductive technological advances. It would further help address ‘silo mentality’ and short-term decision-making and responses to the many challenges we face. In doing so, it would help create new legal frameworks and infrastructure to keep pace with the massive changes that are happening around us, shifting geopolitics and rapidly evolving biopolitics. I also reiterated my call for a new Ministry for Genomics and Fertility, with a dedicated Minister providing unified future direction for the fertility sector, to help develop new integrated national genomic and fertility policy and political strategy.
The International Commission on the Clinical Use of Human Germline Genome Editing
Against this backdrop, I was very interested to read the report published last Thursday (3 September 2020) by the International Commission on clinical application of HHGE. This group was formed in response to the birth of the Chinese gene-edited babies, Lulu and Nana, in November 2018 which exposed the lack of broad international consensus around the acceptability of HHGE technology. The group comprised contributors from 10 different countries, including members of the UK’s Royal Society and the US National Academies of Medicine and Sciences as well as an international oversight board.
This report states that HHGE is not yet sufficiently safe and effective to make gene-edited babies. It makes clear that there is insufficient evidence of high efficiency and specificity to ensure that only the intended changes are introduced into the genome and that there is a continuing risk of off-target edits which could cause significant harm to individuals. This does not come as much of a surprise given the international condemnation that swiftly followed the news of Lulu and Nana’s birth (and a third Chinese gene-edited baby) in November 2018 and early reports that they may have suffered unintended off-target gene edits with unknown consequences.
The report goes on to set out a basis for a future route map for use of this technology should societies deem HHGE acceptable as it becomes more accurate over time. It provides for limited clinical application at a national level. It also encompasses an international scientific advisory panel to assess scientific evidence of safety and efficacy, an international body which would evaluate and make recommendations concerning any proposed new class of use and an international mechanism to enable concerns to be received about research or conduct of HHGE that deviates from established guidelines, transmitted to relevant national authorities and publicly disclosed.
The report’s proposed clinical pathway is framed on a narrowly restricted basis, applying only to prospective parents who could not otherwise have their own healthy genetically related child and those who had already attempted in vitro fertilization in combination with preimplantation genetic testing (PGT) to screen out embryos that carry the faulty version of the gene. In doing so, the report makes clear in its foreword that “Should any nation decide to permit HHGE, it is vitally important that bias and discrimination be avoided. In addition, there must be constraints that prevent the use of HHGE for cases that are not medically justified interventions and not based on rigorous understanding of genetics”.
I note with interest that the report also explains that human gene editing technology takes a range of complex forms, both heritable and non-heritable, and its potential is increasingly being realised and expanded. As such, this technology increasingly cross-cuts both mainstream healthcare and the fertility sector and the report explains that this includes:
- Somatic genome editing – an option already in the early stages of clinical use to treat existing patients with serious monogenic (single gene) genetic disorders and producing promising results including combating Sickle Cell Disease, Beta-Thalassemia and cancer. This application results in genetic changes that are not passed on to future generations. As such, a patient receiving somatic therapy for a genetic disease could still pass the disease-causing mutation on to their future children. This application may also only target a proportion of the relevant cells, requiring additional risk laden treatments like chemotherapy to eliminate remaining cells with the disease genotype. This represents what the scientific and medical communities see as the most acceptable application of human gene editing. However, somatic gene editing therapies are likely to be expensive at the point-of-use treatments in healthcare, albeit there is a wider cost-benefit analysis at play over the longer term.
- Genetic editing of a human zygote – a potential future human reproductive option for editing a single fertilised cell (a zygote) created through IVF which represents the earliest stage of embryonic development. At the zygote stage, it contains only one copy of each of the maternal and paternal chromosome sets and the aim would be to ensure accurate genetic editing for monogenic disorders of both sets to minimise unintended outcomes and maximise the chance of a successful edit before significant DNA replication and cell division takes place. It is currently not accurate enough for human clinical use as we currently lack processes to accurately control the outcome of DNA repair after a gene-induced break is introduced into the genome or accurate processes to analyse the on-target and off-target events in a clinical setting. As such, further research is needed to understand the feasibility and limitations of genome editing in zygotes. If this technique is successfully refined, it could be used in future to prevent monogenic diseases before embryo transfer to include Duchenne Muscular Dystrophy, Beta-Thalassemia, Cystic Fibrosis, Huntington Disease and Tay-Sachs Disease as individuals who inherit these disorders die young or have serious medical problems in life. The incidence of monogenic disease is frequently understood to represent a range of one in 10,000 to one in 1 million births, which is a significant burden from a human health and public healthcare perspective.
- In vitro stem cell-mediated gametogenesis (IVG) – a potential future human reproductive option that marks the intersection of somatic and heritable genome editing. Whilst this has not yet been developed or permitted in clinical use, it offers the potential to develop gene edited gametes (eggs and sperm) from cultured stem cells. This would avoid the issue of cells developing in the embryo with different genetic sequences at the intended target or off-target sites because all embryonic stem cells would be generated from a single genome-edited gamete. However, it also raises wider scientific and ethical issues about the creation, use and potential destruction of many hundreds or even thousands of human embryos created in this way.
- Genome editing in spermatogonial stem cells – a potential future human reproductive option involving sperm cells which originate from stem cells in the seminiferous epithelia of the testis known as spermatagonial stem cells (SSCs). Research has shown in mice that by editing the genome of SSCs and their subsequent transplant into the testis results in the production of sperm with an edited genome. This could be used to prevent human genetic disease being passed on through the male lineage either through natural conception or in subsequent assisted conception treatment.
The International Commission’s report focuses on a route map for clinical application of HHGE from a traditional healthcare and fertility treatment perspective. It makes clear that there needs to be the establishment of a “responsible translational pathway” that is limited and controlled so that scientific and medical communities are not left to self-regulate in the wake of the Chinese CRISPR babies. This approach can be seen from the outset in its foreword to the report where it states “The Commission is concerned that both the development and use of HHGE and allied reproductive technologies (ARTs) must be properly regulated and overseen. In particular, it is important to avoid irresponsible practices in the use of HHGE. In making its recommendations, this Commission has taken into account the unfortunate fact that the practice of ART around the world too often lacks appropriate oversight”.
The Commission’s statement that the practice of ART around the world “too often lacks appropriate oversight” makes for fairly damning reading that does not represent a true picture of the current levels of oversight across the ART sector. The UK leads the world in best practice for regulation of ART through statute and via the fertility treatment licensing system operated and overseen by the Human Fertilisation and Embryology Authority (HFEA). The UK’s position on mitochondrial replacement therapy (‘three-person IVF’) provides a helpful point of reference within the report for future regulation of HHGE and represents progressive law and policy in the field of ART. At the same time, there are checks and balances in place and the HFEA has made clear that 3-person IVF technology will be used cautiously on a case-by-case basis for a small number of people affected by rare genetic diseases. Every country in the EU (albeit slow progress in Ireland) now has legislation governing ART and nearly all supplement this with professional guidance for clinical practice of fertility treatment. In the US, ART is regulated at federal and state level, although there is considerable inter-state variation and some states have limited regulation whilst others have more comprehensive oversight. Professional guidance and good practice therefore plays a significant role in overseeing ART practice in the US. The American Society of Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) also offer professional self-regulation through guidelines and codes of conduct for fertility clinics and their staff. Canada has recently updated its federal regulation of ART and professional guidance also applies to Canadian clinical practice of ART. A number of laws, guidelines and regulations covering ART procedures, research and parentage apply throughout the different states and territories of Australia. In other countries, difficulties and deficiencies remain in legislating and regulating ART as a result of socio-political issues, multiculturism and differing ethical and religious considerations. There are also examples where effective oversight of ART practices does not happen causing very real difficulties and distress for those affected, adverse media coverage and condemnation sparking restrictions and draconian shut down of ART practices as we have seen in relation to international surrogacy in multiple jurisdictions (e.g. India, Nepal, Thailand, Cambodia) in recent years.
At present there is no international harmonisation of law, policy and practice applicable to ART across the EU or indeed the world. The ART sector often operates on a for-profit basis and there are many existing complexities and tensions involving altruistic, commercial, ethical, socio-political and religious considerations. This creates complex international conflicts of law and all manner of logistical difficulties for fertility patients, children and families and significant challenges for law and policy makers in seeking to achieve international consensus and tighter governance of ART. In looking to introduce ‘responsible’ governance of rapidly evolving HHGE practices and allied technologies in combination with existing ART practices, this prevents further significant and complex challenges.
The International Commission’s report states in its foreword that “Great caution must also be taken in the development of genetic technologies like HHGE, fundamentally because of the personal and social contexts and broader societal and ethical issues that surround their application. Proposed uses of these technologies must reflect the conditions and needs of diverse human populations around the world. They should be deployed in ways that prevent harm and ensure equitable access to their benefits. The technologies themselves and the rigorous oversight structures established to regulate their use should be developed in ways that respect the human rights and inherent dignity of all persons”. However, the report does not address in any detail the wider issues, risks and ramifications of rogue scientists, clinicians and states utilising human gene editing technology (both heritable and non-heritable) on national security, public health and healthcare, the economy or its ramifications in combination with rapidly evolving digital and artificial intelligence considerations. As such, despite its detailed analysis that spans over 200 pages and its proposed framework for clinical application, the report does not adequately take into account the risks that individuals, organisations and states will not sign up to it, or that they will simply pay lip service to it and undertake HHGE and allied technologies covertly or hide in plain sight on their own wider terms. Surprisingly, it does not set out any sanctions for non-cooperation or non-compliance with the proposed framework.
It remains the case that gene editing technology (both human and microbial) raises ongoing serious and fundamental issues from a national security perspective. Many countries currently prohibit HHGE in the creation of genetically modified humans, as is the case in the UK and the US. However, some counties have no laws prohibiting the use of HHGE and allied technologies and this remains a palpable concern. In the absence of effective international consensus and governance jurisdictions could develop different paradigms, have a change of mind and adopt different approaches to use of this powerful technology. What one state considers to be irresponsible use of human gene editing technology (heritable and non-heritable) another state could see as a responsible way of protecting their national interest. Whilst the creation of gene edited adult humans with enhanced attributes who could be used for malfeasance is for many simply unthinkable and the subject of science fiction, it remains a possibility in reality. We run the risk that gene editing programmes (both human and microbial) could operate ‘under the radar’ or hide in plain sight in some jurisdictions. This risks nefarious activity and use of this powerful technology (heritable or otherwise) leading to the development and release of biohazards that are genetically engineered with the capability to kill and decimate populations and nations, incapacitate or render people infertile in the short as well as medium and longer term. It could also lead to the creation of genetically enhanced human cohorts (e.g. who have enhanced intelligence, strength or resistance to disease) who could be used against or to infiltrate nations across the world for advantage and gain. Some jurisdictions could even potentially want to use this technology to achieve a genetically enhanced human population in order to bolster their national defence capability, achieve a healthier population, develop a more productive workforce and gain greater global influence. This adds further layers of complexity to geopolitical and rapidly evolving biopolitical considerations at play within the overall debate about the appropriate use and regulation of human gene editing technology, both heritable and non-heritable.
The International Commission also states in its foreword that “There is no doubt that the economic costs of developing and using this technology will be substantial. Moreover, since there are already viable alternatives for prospective parents to have genetically-related, unaffected offspring in the vast majority of cases, the benefits will accrue to very few prospective parents. Nonetheless, it is possible that HHGE might someday become sufficiently safe, robust and efficient to be routinely applied in conjunction with ART to provide an improved option that would reduce the burden to women of repeated cycles of ovarian stimulation”. In adopting such a narrow view, this restricts investment, research and development of human gene editing technology and pushes back in time the “someday” where it could be applied more widely in practice.
The report states that the “costs of developing and using this technology will be substantial”. Whilst research into this technology requires investment, genetic sequencing now costs just a few hundred pounds per genome, making it increasingly affordable and capable of integration into mainstream healthcare and fertility delivery. Costs of genetic analysis and interpretation are on top, but costs will fall in the coming years. If genomic sequencing, analysis and subsequent editing costs say £5,000.00 – £10,000.00, it still makes economic sense. It is far cheaper than the cost of treating a sick child or adult suffering from genetic disease and lost productivity in the workplace. It is likely to decrease the costs of institutionalised care and result in healthier people living better quality of lives. This in turn is likely to increase GDP and lead to greater innovation and development of society as a whole. Human Gene editing technology, both heritable and non-heritable, therefore has the potential to generate significant wealth, power and influence for individuals, businesses and nation states.
Human gene editing technology should not therefore simply be seen from a limited fertility treatment and healthcare perspective. It is not just a technology that can be developed and used to help small numbers of prospective parents avoid the incidence of serious genetic diseases in their genetic offspring or help treat people suffering with serious and deadly genetic diseases. Used carefully and appropriately as this technology develops and improves, it offers wider potential benefits for prospective parents, their children, future generations and societies around the world. Genomic science, medicine and fertility treatment of the future has the potential to significantly reduce disease, pain and suffering and create healthier populations, increase revenue for the fertility sector and state GDP. It could also help address fundamental societal issues of declining fertility levels, sub-fertility, later-life conceptions and ageing populations and associated declining health levels.
This adds wider dimensions to the debate about the motives, use, benefits and risks of gene editing technology involving heritable and non-heritable human application and also microbial usage. It requires understanding and interpretation of these wider factors too, as they are also likely to influence, shape and change the paradigms in which individuals, organisations and nations will approach human gene editing technology moving forward. The issues, benefits and risks are multi-faceted and if we are to effectively use and regulate this technology it will require us to shift our paradigms.
Summary
The International Commission’s report represents a missed opportunity to expand and shift its paradigm and assess human gene editing technology (heritable and non-heritable) in an integrated context that takes wider account of the ongoing rapidly evolving digital, artificial intelligence, genomic, science, epigenetic and human reproductive revolutions. Gene editing technology, like CRISPR-Cas9 or prime editing, is a genetically programmable system with immense potential. We must not underestimate the allure of using this powerful technology to achieve a healthy child, for human genetic enhancement or other reasons.
As human gene editing technology expands and improves, we are also likely to see a corresponding shift in perception towards an ethical obligation to have a healthy child through genetically planned parenthood. This technology will help alleviate a biological lottery at birth, avoid condemning children and adults to preventable disease, pain and suffering and has the potential to give a child a ‘head start’ and better opportunities in life.
How this technology is used and regulated therefore requires informed public debate and decision-making. We need new law and policy frameworks to address its transformational capability as we increasingly have the capacity to change and control the human condition through gene editing technology. The ongoing digital, artificial, genomic and epigenetic advances will accelerate the human reproductive revolution intensely and rapidly in the absence of new law and policy frameworks. We will require new laws for new kinds of family creation as people seek to avoid genetic roulette. This will involve root and branch law reform and centralised legal regulation as we move from healthcare to health design.
Law and policy makers will need to address a range of economic issues around this technological revolution. This will require renewed debate about price regulation, whether genomic medicine and fertility treatment should be free at the point of access, subsidised by the state or privately funded. There will also need to be debate about the costs of future investment in this rapidly evolving technology, revenue and profit generation, the commercial value of genomic knowledge, datasets, science and changes in GDP.
It is also critical for future law and policy frameworks to tackle the dark side of gene editing technology and its relationship with national security and public health now and into the future. The permanent and irreversible nature of changes to the human gene pool using HHGE and the wider application of gene editing technology (both human and microbial) has the capacity to be used for harm as well as good. The science is here now and a robust framework is therefore needed now.
It will therefore be important to see what law and policy decisions, frameworks and sanctions for non-compliance are taken in countries across the globe in light of the current science, the International Commission’s report on human gene editing and the report by the WHO expected later this year. It will require concerted engagement and commitment to ensure law and policy makers build effective legal and regulatory frameworks that will safely and successfully harness the enormous transformational power of gene editing technology. Integrated multi-disciplinary success is within reach but only if we widen and shift our paradigms to achieve enlightened root and branch law and policy reform that dismantles ‘silo mentality’ and encompasses all the forces at play globally.
Need a fertility lawyer? For further information and assistance contact Louisa Ghevaert by email louisa@louisaghevaertassociates.co.uk or by telephone 44 (0)20 7965 8399.
