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CRISPR immunity: a case study for justified somatic genetic modification?
  1. Eli Y Adashi1,
  2. Ivan Glenn Cohen2
  1. 1 Medical Science, Brown University, Providence, Rhode Island, USA
  2. 2 Harvard Law School, Cambridge, Massachusetts, USA
  1. Correspondence to Professor Eli Y Adashi, Medical Science, Brown University, Providence, RI 02906, USA; eli_adashi{at}brown.edu

Abstract

The current SARS-CoV-2 pandemic has killed thousands across the world. SARS-CoV-2 is the latest but surely not the last such global pandemic we will face. The biomedical response to such pandemics includes treatment, vaccination, and so on. In this paper, though, we argue that it is time to consider an additional strategy: the somatic (non-heritable) enhancement of human immunity. We argue for this approach and consider bioethics objections we believe can be overcome.

  • clinical ethics
  • enhancement
  • ethics
  • genetic engineering

Data availability statement

There are no data in this work.

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One of the greatest human health innovations of all time would be to make ourselves multivirus resistant-render ourselves immune to all viruses, known or unknown, whether currently existing or waiting in the wings.’ —George M Church and Edward Regis, Jr1

Down through the ages, pandemics have repeatedly exacted a heavy toll on human life. The deadliest such affliction may well have been the 1918 influenza pandemic which is estimated to have claimed a total of 50 million lives worldwide. The current SARS-CoV-2 pandemic is on track to kill millions. While SARS-CoV-2 has been viewed by some as a ‘black swan’ in its R0, modes of transmission and the way it has interacted with existing public policy, it may also be a sign of things to come. These pandemics are an evolutionary inevitability because random mutations transform otherwise harmless life forms into potent pathogens, a threat for which the adaptive human immunity system is far too slow to counter. Without applicable antiviral therapeutics, a vulnerable humanity will have to contend with future pandemics with its hands tied. It is against this backdrop that we argue that somatic (non-heritable) enhancement of active, passive and cell-mediated immunity is a goal worth pursuing as a strategy for this and future pandemics.

The somatic enhancement of active immunity against SARS-CoV-2 is presently in a holding pattern pending the development, production and roll-out of a safe and effective vaccine (with great progress occurring at the time of this writing). Conventional vaccines are indispensable by dint of their capacity to stave off resurgent viral offenders. Numerous SARS-CoV-2 vaccine candidates are presently in various stages of development: genetically modified viral vector-based vaccines and plasmid DNA vaccines constitute especially promising entrants. While there is hope that access to vaccines for COVID-19 will be achievable in the medium term, this pandemic has taught us the prolonged time frame required for the generation of safe and effective vaccines precludes their use at the outset of a deadly outbreak. In search of alternatives, increasing attention is being accorded to the somatic enhancement of passive immunity by way of polyclonal or monoclonal antibodies. In one such early effort, primary human B lymphocytes were CRISPR edited to yield polyclonal antibodies aimed at several viral threats.2 Highly specific human monoclonal antibodies, in turn, have gone as far as the clinic and their utility has been affirmed. In one highly publicised case, potent human monoclonal antibodies effectively countered symptomatic Ebola virus infections.3 Comparable hopes are being pinned on human monoclonal antibodies to SARS-CoV-2 the in vitro efficacy of which was recently documented.4 For all their promise, however, the capacity of monoclonal antibodies to confer passive immunity is short lived and thus in need of intermittent replacement. It remains to be seen if such limitations can be overcome. There is also active exploration of organ-specific delivery of monoclonal antibodies. One such promising line of research involves humanised llama-produced ‘nanobodies’ the stability of which may permit direct inhaler-mediated delivery to the lungs.

There is, however, another tool potentially available: the somatic enhancement of cell-mediated immunity to combat SARS-CoV-2. Such viral containment efforts would be taking a page from the field of oncology where autologous genetically engineered T lymphocytes revolutionised the care of cancer. Comparably modified autologous T lymphocytes were also applied to the treatment of the HIV. Reliance on such CRISPR-edited cellular therapeutics for the treatment of acutely ill patients with SARS-CoV-2 is just a matter of time.5 One of the benefits of this type of cell therapy is its longevity in that recipients are afforded with cell-mediated antiviral immunity for well over a decade.6 Apart and distinct from the aforementioned cell-mediated therapy, early consideration is being given to the direct in vivo delivery of CRISPR and its guide RNAs to key SARS-CoV-2-affected tissues.7 These and related CRISPR-based strategies require that genes essential to the life-cycle of the virus and those that predispose its human host be identified.8 9 Laboratory-based efforts to this end are well underway.8 Parallel ‘big data’ efforts have also taken off under the auspices of the COVID Human Genetic Effort, COVID-19 Host Genetics Initiative, NHLBI LungMAP Consortium, Human Cell Atlas Lung Biological Network, 23andMe and Ancestry.

From a bioethics standpoint, should such efforts worry us? These are, after all, in a manner of speaking a form of human ‘enhancement’—although one to confer immunity. The notion of genetically enhanced beings has been the subject of debate since the dawning of gene therapy.10 Many of the key objections, though, fail to reach the kind of editing we discuss. Human enhancement via germline (heritable) genome editing, the subject of ethical, religious and societal objections, continues to engender significant controversy.11 There are a series of objections that have been raised against germline enhancement. These include the potential to disfigure the parent–child relationship, the transformation of reproduction into manufacture, the contravention of a ‘right to an open future’ and lack of creativity in the choices we make.12–17 None of these are implicated by somatic alteration, which would be done by an individual on themselves (or in the case of minors under the age of consent would follow the same rules that apply to surgical and other interventions).

What is more, it is clear that somatic alteration, if successful, confers a benefit to the individual in question. This is in contrast to thorny questions for the concept of benefit in germline editing associated with Derek Parfit’s non-identity problem: in the germline setting one must make difficult determinations of when alterations are identity preserving—and thus making a particular person better off, person-affecting reasons for acting—versus alterations that are identity disrupting and creating different people—and thus providing only non-person-affecting reasons for acting, as well as evaluate when enhancement can be justified only on non-person-affecting reasons.18–20 What is more somatic editing to confer COVID-19 immunity benefits the person who is edited and those around him due to considerations of herd immunity. Therefore, this represents a case of positive not negative ‘reproductive externalities’; it is the latter that might raise concerns where the benefit inures to the person being altered but the costs are transferred to others, a circumstance not present in this case.20

By contrast to germline editing, somatic (non-heritable) enhancement is commonly viewed through beneficent prisms where disease prevention is top of mind.21 A report of the National Academy of Medicine reached similar conclusions when noting that ‘somatic gene and cell therapies are widely seen as morally acceptable’.22

If we are right that many of these objections to germline editing will not apply in this context and there is so much potential good for these somatic alterations, what are the ethical concerns? In what follows, we discuss a four of them: safety, cost and distribution, how to accommodate those who are unable or unwilling to pursue the alteration and the threat to overall social solidarity raised by the potential for such alterations.

Safety, of course, is a prerequisite and any attempt at conferring CRISPR immunity would require in-depth study and regulatory review before it should be considered. As with the recent vaccine trials, trial design would be important and raise a series of research ethics questions such as identifying appropriate thresholds for effectiveness, when to conduct interim analyses, when to use and stop using placebo controls and whether so-called ‘challenge trial’ designs would be appropriate.

Who would pay for these alterations also requires attention—if left to the private market and priced high, one might worry that it would worsen distributional inequality with only the wealthy able to return to normal life through the alteration—a reason to consider public provision or at least mandated insurance coverage. The recent COVID-19 vaccine trials suggest some promising models—public investment in development in exchange for certain pricing guarantees and/or purchase precommitments.

A related and very difficult question concerns when the voluntary can become, by market forces, compulsory. That is, even absent a state mandate to undergo somatic alteration, individuals might feel significant pressure to do so if access to important social goods such as some jobs, education, and so on is conditioned on demonstration of immunity as in a so-called ‘immunity license’ or ‘immunity passport’ regime.23 24 Whether such a regime is problematic might depend on an institution-by-institution analysis of whether the institution may justly demand immunity as a condition of participation (compare, for example, vaccination mandates for schools which are widely accepted as just though ‘expire’ after a period of time unlike a somatic alteration).

Even if just overall, thought would have to be given about what to do about those who are unable (by dint of other medical condition) or unwilling (because of religious objection or another reason) to have the somatic alteration but still make a claim to access the institution or good in question. Such questions are not easy. They raise multiple types of questions: there are empirical questions such as determining who in fact is unable to undergo a somatic alteration and how that could be verified. There are many legal questions. For example, how should the state determine when a religious or non-religious objection to alteration will be treated as requiring an exemption from an otherwise broadly applicable requirement? How do existing antidiscrimination laws treat claims for protection by those who are healthy but who are unable or refusing to reduce their risk by getting alteration? There are administrability questions, such as which institutions get to condition access on proof of protective alteration and on what evidentiary basis, and when those access conditions should/must be altered when there are changes in the prevalence of the underlying disease or the availability of therapeutics?

But while these questions are hard, they are not unfamiliar. Many of the same issues present themselves in the vaccination context—for example, whether a public school can condition student participation on the student being vaccinated against a particular disease. Some have argued for an obligation to be vaccinated as part of a ‘fair share’ obligation as to a collective good.25 The way to think about this problem would be to draw appropriate parallels to the same legal and ethical analyses in the vaccination mandate context, while considering how safety or irreversibility concerns may play differently with somatic alterations.

One thing that is (if not unique) at least somewhat distinctive about the COVID-19 pandemic has been large number of opportunities cut-off to individuals in the status quo non-immunity state, opportunities that would be opened in a regime of effective somatic alteration but only to those who pursue the alteration. That is, unlike vaccination mandates which close the door on some particular (although very important) ways of pursuing a good life (eg, requiring those working in healthcare to be vaccinated but not those working at social media companies), pandemics threaten to shut those without immunity out of public life in a much more wholesale way. The pressure to pursue such somatic alterations is much more forceful, because those who choose not to seek immunity might truly be ‘left behind’ unless and until other effective treatments/preventions are available, and indeed the public support and funding for such treatments/preventions is likely to be reduced if most pursue somatic alteration that proves effective. When the door to anything resembling a good life requires as its key a somatic alteration, can we really say that individuals are voluntarily choosing the somatic alteration?

In our view, the answer is yes if we can ensure that the availability of somatic alteration does not reduce the need for solidaristic support of those who refuse alteration and get COVID-19 or must remain outside of employment or public life. States would need to make credible commitment must not reduce their entitlement to COVID-19 care or financial support on the argument that it ‘was their fault’ for not getting an alteration. That is, the reason to offer care or other support to these individuals is not diminished in a blanket way by the fact that they chose not to get the alteration. In the case of those who face particularised safety risks that cause them to avoid the alteration, the argument for resisting reducing solidaristic support is straightforward—it was truly ‘not their fault’ that they had the condition making it unsafe (or at least less safe) for them. In the case of those with religious or other objections, the question will depend more on underlying facts and also one’s tolerance for luck egalitarian arguments for healthcare distribution as well as one’s weighting of religious or moral objections.16 19 23 One hope is that somatic alteration, if successful, will allow many (if not all) ‘boats to rise’ such that it will free up resources rather than cause us to have to cut back, and for that reason enable us to avoid the impulse to ‘penalize’ the unaltered with reduced support.

For all of these reasons, it follows that the somatic enhancement of immunity, one spanning the traditional boundaries of medicine, is best viewed as a desirable goal to pursue. Indeed, the key ethical debates are likely not to focus on whether it is permissible to pursue such enhancement, but instead questions of safety, cost, distribution, accommodation of those who are unable or unwilling to pursue the alteration and the threat to overall social solidarity raised by the potential for such. Whether or not immunity ‘to all viruses, known or unknown’ is attainable remains to be seen.26

Data availability statement

There are no data in this work.

Ethics statements

Patient consent for publication

References

Footnotes

  • Twitter @cohenProf

  • Contributors Both authors contributed equally to the writing of the submitted manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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