On Tuesday, a report a year in the making on human genome editing was released, prompting media coverage from just about everywhere. Whereas this report’s predecessor said it would be “irresponsible to proceed” with clinical human germline modification without “broad societal consensus, this update recommends against a prohibition.
In this post, I discuss how they couch this recommendation. Ultimately, I don’t think they offer any convincing arguments for the shift in attitude. While the debate is still hypothetical (there are ongoing scientific issues; the practice is currently illegal in the US), this report does have the ability to “change the tone” on the use of the technology, and it has seized that opportunity.
Published by the National Academy of Science and the National Academy of Medicine, the report follows on from the International Summit on Human Gene Editing, convened in December 2015. The broad purpose of the efforts are to respond to the rapid technological advancement of genome-editing tools (particularly CRISPR-Cas9): to consider their potential medical uses, and the ethical, social and legal issues that arise.
For all research applications, the authors contend that existing ethical norms and regulatory frameworks will work just fine1.
Recommendations for clinical applications are organised under two main distinctions: Somatic (non-heritable) versus Germline (heritable), and Therapy versus Enhancement. The recommendations:
||Existing ethical norms and regulatory regimes satisfactory2
||Do not proceed at this time; engage with the public
||Approach with caution, but do not prohibit; ensure stringent oversight system3
It was the failure to recommend an outright ban on germline modification that caused some surprise. As Francis Collins, Director of the NIH, noted in 2015, the “concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed”. And as the authors state in the report: “Given how long modifying the germline has been at the center of debates about moral boundaries, as well as the pluralism of values in society, it would be surprising if everyone were to agree with this recommendation.”
In addition to putting frameworks in place to ensure due consideration of health and safety concerns, the authors want to ensure
- there are no “reasonable alternatives”
- societal benefits and risks are balanced, and that the public should be involved in this process
- the principle of transnational cooperation is adhered to
- there are “reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition”
I expand on these considerations below. I also look at the strategies for public engagement they propose.
When would there be no “reasonable alternative” to germline genome modification?
In brief, prenatal genetic diagnosis (PGD) – which is routinely offered as part of an IVF cycle – would almost always be a reasonable alternative to germline modification, because selection of embryos will suffice to prevent the birth of individuals with severe genetic disease. Hank Greely makes this case in his book “The End of Sex”. There is one exception involving the incredibly rare case of co-dominance.4
The authors give two other potential scenarios under which there would be no reasonable alternative to germline genome modification. One is that PGD involves “discarding affected embryos, which some find unacceptable”. This is hard to take seriously. Germline modification would also involve an IVF cycle, and not all embryos that get produced in a cycle are implanted, PGD or no. In other words, it seems hard to imagine someone who would be okay with the use of germline editing, but not with the use of PGD.
The authors argue that germline genomic modification could also be the only option as it could increase the number of viable embryos available for implantation — lack of viable embryos is a common failure mode for IVF cycles, and PGD reduces this number yet further. This seems to me to be a more reasonable consideration. However, this would assume the technology was perfect, and that prospects on the horizon such as using stem cells to make egg cells do not materialize.
All of this of course assumes that being something other than the biological parent of a child is not a “reasonable alternative”.
Balancing societal benefits and risks and involving the public
This report explicitly aimed to continue the dialogue initiated by an earlier effort, which concluded in December 2015 that it would be “irresponsible to proceed” with clinical human germline modification without “broad societal consensus”. This report, in contrast, calls for “continued reassessment of both health and societal benefits and risks, with broad on-going participation and input by the public” – a significant watering down of the importance of public opinion and attitudes to impact on society.
Embracing their own methodology of a risk-benefit analysis (which is far from the only take), how do the benefits and risks of the use of germline genomic modification stack up?
Benefits the report mentions are:
- Enabling prospective parents to have biological children free from serious disease (assuming no other alternative). It could be argued that this is a fundamental right in need of protection. “The number of people… might be small, but the concerns of people facing these difficult choices are real.”
- The creation of a more level playing field for those whose traits put their children at a disadvantage
- Public health benefits (though note these same benefits prompted the eugenics abuses of the past)
Potential risks mentioned fall under several themes:
- Inability to prevent inappropriate or abusive applications
- Recurrence of the abusive forms of eugenics practiced in the past
- Further stigmatization of disability
- Exacerbation of social inequalities
- Creation of social pressure for people to use technologies they would not otherwise choose
- Children being seen as “constructed products”
- Parents increasingly viewed as responsible for the qualities of their offspring
The authors note that whereas most of the benefits accrue to individuals and are more immediate in nature, the risks mostly relate to society and are more diffuse. Because of this, arguments for the benefits and risks “can fail to engage each other directly.” That the benefits are more immediate can end up shaping how the risks are perceived: new technologies cause cultural change, partially mediated by the fact that individual decisions change societal norms. Regulations are based on cultural views, and, as the authors themselves note “it is the underlying change in cultural views that is precisely the slippery slope”. In other words, although the risks seem more diffuse, unless we give them due weight now, the sands will have shifted with early application of the technology, and we may find ourselves committed to a particular type of future.
Marcy Darnovsky, executive director of the Center for Genetics and Society, states that although the report does acknowledge the risks, “Strangely, there’s no apparent connection between those dire risks and the recommendation to move ahead.”5 I would agree that while the report is clearly written, it is often unclear how the recommendations arise out of the considerations raised.
Even if one agreed with the recommendation to “proceed with caution”, it still seems at odds with the very strong emphasis on the importance of public engagement throughout the report. Edward Lanphier, chairman of the DNA editing company Sangamo Therapeutics argues: “It changes the tone to an affirmative position in the absence of the broad public debate this report calls for.”6 Another example of the report not coming across as entirely internally consistent.
Science and technology are transnational pursuits, but how we chose to apply them to our societies is necessarily contextual: “It is important to note that such concepts as “reasonable alternatives” and “serious disease or condition” embedded in these criteria are necessarily vague. Different societies will interpret these concepts in the context of their diverse historical, cultural, and social characteristics, taking into account input from their publics and their relevant regulatory authorities.”
The authors simultaneously call both for respect of cultural differences, and the promotion of regulatory standards. The latter is necessary to prevent medical tourism.7 The authors conclude their chapter on Germline modification with the observation that the current US legislation that prohibits the practice serves “to drive development of this technology to other jurisdictions, some regulated and others not.” It is unclear how much this consideration motivates the recommendation to “proceed with caution”. Bioethicist George Annas finds this position unconvincing: “the fact that something could be done even if outlawed is hardly a [reason] not to outlaw it if you think it should not be done.”8
I very much appreciated that the report actually gave some examples of cultural attitudes that could influence perspectives on genomic modification. We are familiar with the fear of “Playing God” from the Christian tradition. In contrast the authors note that: “In the Jewish tradition, on the other hand, there is an explicit obligation to build and develop the world in any way that is beneficial to people, and such improvements are viewed as a positive collaboration between God and humans, not as an interference with creation. Similarly, many Muslims and Buddhists view genetic engineering as just one of many welcome interventions to reduce suffering from disease”.
What of the distinction between Curing Disease and Enhancement?
The report does a good job of illustrating just how hard it is to draw the line between curing disease and enhancement, including:
- What should be considered “natural” or “normal”?
- What of preventative, rather than curative, measures (e.g. reducing chances of developing a disease or contracting an infection)?
- What counts as a disease (homosexuality used to)?
- What about late onset diseases?
At the very least, we need some concept of a “problematic enhancement” – perhaps one that “confers a social advantage beyond that which an individual possesses by fate or through personal effort, and that does not benefit the rest of society in any way or undermines the implicit goals of a competition.”
The authors state that: “Of course, somatic or germline genome editing for enhancement is very unlikely to be the most profound source of inequality in any setting.”
In the US off-label drug use is generally permitted. The authors give one example, of genomic modification for muscular dystrophy being of interest to those who wish to become even stronger. They go on to state that “other examples are more difficult to envision” – something that may well turn out to be a failure of imagination.
Given the above, how “reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition” could be envisioned is left by the report authors as an exercise for the reader.
There is another option for public policy that the authors note – work to make advantageous enhancements broadly available.
Strategies for Engaging the Public
The authors state that: “A robust public discussion about the values to be placed on the benefits and risks of heritable germline editing is needed now so that these values can be incorporated as appropriate into the risk/benefit assessments that will precede any decision about whether to authorize clinical trials.”
Two of the main components in the approval of clinical trials are Institutional Review Boards (IRBs) and the FDA, and neither considers societal implications: IRBs are explicitly forbidden from doing so, and the FDA has no statutory mandate to consider public views.
There is a committee that considers public opinion and societal impact, the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC). It publishes non-binding guidelines. It does have public review, intended “to enhance public awareness of and build public trust in such research, allowing for a public voice in the review of the research”. Which sounds suspiciously like “educate the public about what’s good for them”.
The report argues that we will need more formalized efforts than are currently in place to enable the robust discussion called for, and that federal agencies “would need to consider” funding such efforts. Although they do go into detail about what this public engagement could look like, this call to action could have been considerably stronger.
I would summarize the landscape thus. There are 1 in a million9 people that cannot have biological children free of serious disease unless use of this technology is approved. Once this technology is developed for this use case, the technological barriers to applying it in other use cases, including for enhancement, will be low. The societal barriers will also likely be lowered. There is a concern of a slippery slope to applications that challenge our current societal values. There is also the possibility that other jurisdictions will authorize this technology. We need to involve the public in this discussion now.
On the report itself: It is very comprehensive and covers a lot of ground in a thoughtful manner; Perhaps inevitably given that it was written by 20 people, it is not always clear how the issues raised are aggregated into the overall recommendations.
- The excitement around CRISPR-Cas9 and germline modification has eclipsed the fact that the cases in which it would bring benefit over preimplantation genetic diagnosis are few
- The “proceed with caution” recommendation for germline modification is at odds with an insistence on public debate
- I come away from the report further convinced that a slippery slope from curing severe disease to enhancement is inevitable
For these reasons, I do not support the shift in tone from prohibition to “proceed with caution”. Additionally, an opportunity has been missed to make a more actionable call to promote public discourse, particularly around funding of this research.
The report, at 150 pages long plus appendices, not a short read, but it is very accessible, and gives digestible overview both of the current state of the science and of several of the bioethical themes. Recommended reading!
1 In the US, there is a bar on federal funding being used in any research that involves destroying human embryos. In other countries, such as the UK and Sweden, there are no such bars and research is ongoing.
2 My co-author Sarah Polcz and I have argued that there are issues in somatic application worthy of particular attention, for example consent issues for minors.
3 Note that due to a budgetary provision in effect until at least April 2017, the FDA cannot consider clinical trials involving germline genetic modification, making the practice illegal.
4 The reasons that PGD suffices in almost all cases comes from basic principles of inheritance of genetic conditions: the fact that you get two copies of every gene, one from Mum and one from Dad, means that for dominant diseases (where one bad copy leads to disease), you make sure not to select the one in two embryos that have that one copy, and for recessive disease (where you need a bad copy of both genes) when both parents have one bad copy, you just make sure to not select the one in four that inherits both bad copies. There is one scenario that PGD would not work for: one of the parents has a dominant disorder, but actually has TWO bad copies of the gene. In this case, no embryos would be free from disease. Such “co-dominance” is exceptionally rare.
5 Quoted in an article in the Washington Post
6 Quoted in an article in Science
7 I can’t help but mention that in the utopia of the Star Trek universe, the Federation bans genetic modification for all except the correction of severe genetic disease. However, as Dr Bashir’s parents knew, there were some planets on the outer reaches of Federation territory where you could go to improve your genetics…
8 Quoted in an article in STAT
9 I made this number up based on an incredibly generous estimate of how many individuals with co-dominant alleles for severe diseases there are