Editing the germline – a time for reason, not emotion

Gyngell, Douglas, Savulescu

There are rumours in the scientific community that the first studies involving the genetic modification of a human embryo are about to be published.[1] If true this would be the first case of an experiment in which genes in germ cells (sperm and egg cells) have been intentionally modified.  This has caused some concerns in the scientific community due to the fact that these modification are potentially heritable.  A commentary in Nature, (written by four leading scientists and one philosopher) published an appeal that we “Don’t edit the human germ line”.  Science meanwhile published a commentary which outlines “A prudent path forward for genomic engineering and germline gene modification”. The fact that two of the world’s most prestigious journals are publishing commentaries on human genetic modification shows just how powerful gene editing techniques have become. The rapid speed with which these technologies have developed has taken the scientific community, and everyone else, by surprise. Just three years after the DNA cutting nuclease Cas-9 was first used to modify DNA, scientists have been able to make heritable modifications to yeast, plants, mice, rats, pigs and even primates. It has been claimed that experiments conducted in China, currently under review, have used these same technologies to modify the DNA of human embryos.[2]

Although the reality of human germline modification may be a surprise, we should resist making any knee-jerk reactions or judgements. Both the Nature and Science commentaries do just this, and fail to provide a good starting point for an informed discussion about the ethics of germline editing.  Both advocate for clear actions but neither justify these actions by clear reasoning.

The Nature commentary calls for a moratorium on gene editing. Below are some of the passages from it:

In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations. This makes it dangerous and ethically unacceptable. Such research could be exploited for non-therapeutic modifications

The CRISPR technique has dramatically expanded research on genome editing. But we cannot imagine a situation in which its use in human embryos would offer a therapeutic benefit over existing and developing methods.

Many oppose germline modification on the grounds that permitting even unambiguously therapeutic interventions could start us down a path towards non-therapeutic genetic enhancement. We share these concerns.

While these statements appeal to broad concerns about germline editing, they do not provide clear reasons to resist or restrict it. Many technologies have unpredictable effects on future generations but this does not mean they are either dangerous or morally unacceptable. Who can predict the effect of information technologies like the internet or smart phones on future generations?

One might object that such technologies don’t operate at the genetic level, like CRISPR, and are not passed heritably down to the next generation. But this is a deep mistake – environmental interventions, such as modified social interaction, have epigenetic effects, modify brain development and can be passed on to the next generation.[3]

Another example is IVF and pre-implantation genetic diagnosis (PGD). PGD requires removing two cells from the 8 cell embryo. It excises 1/4 of the embryo. This could have been much more devastating than gene editing yet it has been proven to be safe. Nevertheless, when introduced it was certainly unpredictable what the effects would be for future generations.

Similarly many new technologies are non-therapeutic but this rarely warrants a moratorium on their use. While many medical technologies are only approved for use in a therapeutic setting, the mere fact that a technology could be used non-therapeutically does not justify placing broad restrictions on it. Lasik eye surgery can be used non-therapeutically, but this doesn’t justify restrictions on its therapeutic uses.

In short, the Nature commentary fails to justify why germline editing deserves to be treated specially. Why do general concerns about this technology warrant such extraordinary disapproval, while the same concerns in other technologies are ignored?

The authors’ failure to recognise that to justify a moratorium they need to provide arguments that germline editing deserves special attention is especially apparent in their discussion of the possible safety risks of gene editing:

It would be difficult to control exactly how many cells are modified. Increasing the dose of nuclease used would increase the likelihood that the mutated gene will be corrected, but also raise the risk of cuts being made elsewhere in the genome

The current ability to perform quality controls on only a subset of cells means that the precise effects of genetic modification to an embryo may be impossible to know until after birth. Even then, potential problems may not surface for years.

Under agreed global research ethics standards, no experiments should be conducted where there is a high risk of harm to the participant, and a low chance of benefit. Hence if germline editing posed a risk due to off-target mutations or possible unknown effects and promised little or no benefits, such studies should not be approved. This is true for all research involving human subjects. Pointing to safety risks with germline editing, then, explains why such research is unlikely to get approved under existing research ethics protocols.  It does not justify why this technology should be treated differently to others.

Moreover, the commentary seriously underplays the potential benefit of CRISPR. Its authors claim that they

cannot imagine a situation in which its use in human embryos would offer a therapeutic benefit over existing and developing methods.

This speaks more to the limitations of the imagination of the authors than the limitations of the science.  Gene editing techniques hold the promise of curing genetic defects such as cystic fibrosis, thalassaemia, Huntington Disease, and some forms of Alzheimer’s disease. Currently, the only available way to prevent genetic disorders involves using IVF and PGD. But this technique does not provide a therapeutic benefit, it merely prevents individuals who would have had a genetic disease from coming into existence. In contrast gene editing could provide genuine benefits to future people by curing them of their genetic disease at the embryonic stage.

Furthermore the power of IVF and PGD is severely limited. Some couples will only produce a single embryo through IVF, and so selection is not an option. Even when multiple embryos are produced, the number is small (typically around 7 per cycle).  This places tights constraints on the number of health related traits that can be targeted simultaneously.  All of us have hundreds of genetic limitations or dispositions to disease that make it more likely we will get cancer, heart disease, dementia etc. If a couple want to use PGD to select for 20 different desirable genes in an embryo, they would need to create around 10,000 embryos to make it sufficiently likely that one will have the right combination at all 20 loci.[4] This is not possible with current IVF technologies.  Gene editing provides a way to iron out all of our genetic wrinkles. All could live much longer and healthier in a world of effective gene editing.

The Science commentary is far more measured. However, in calling for germline editing to be “strongly discouraged” it too needs to explain why germline editing deserves special attention.  Why bother discouraging germline editing, when risky and unsafe research is already universally discouraged? Take the below passage

At present, the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever, for clinical testing

While this is a good point, it is an obvious point. When do we not need to understand the potential safety or efficacy issues of a technology before sanctioning it for clinical testing?

A key fact noticeably absent from both the Nature and Science commentaries is that many other human activities cause modifications to the human germline. Smoking tobacco, for example, causes mutations in the DNA of sperm which are then be passed on to the next generation.[5] Older fathers tend to pass more germline mutations on to their children than young fathers, meaning delaying paternity also increases the rate at which mutations accumulate in the human germline.[6] The only difference is that these mutations are completely random, whereas gene editing is intentional. But if anything this should make editing more attractive. Random mutations are always indifferent to human happiness and flourishing, unlike intentional modifications. Any attempt to justify restrictions on gene editing needs to clearly explain why the risks associated with germline modifications are so great that they justify restrictions on potentially life-saving research, but do not justify restrictions of parental age, or the lifestyle habits of potential fathers.

Another feature shared by both commentaries is that some of the authors of each piece are founders, CEOs or senior executives of private companies involved in gene editing on somatic cells. Unlike modification to germ cells, modifications in somatic cells are not heritable. These companies would likely be devastated by any broad restrictions on gene editing. This means the authors have skin in the game – they might be personally benefited by bans on germline modification if this development made restrictions on somatic editing less likely. This may be on the mind on the authors of the Nature piece, as seen by this comment:

We are concerned that a public outcry about such an ethical breach could hinder a promising area of therapeutic development, namely making genetic changes that cannot be inherited.

But even if these authors have valid concerns about unreasonable restrictions on somatic editing, creating emotive panic about germline editing is a poor response.  We should not cast aspersions on germline editing just to take the focus off somatic editing. We need to ensure good decisions are made regarding the regulation and use of both technologies.

Our central point in this blog is that all of the concerns that have so far been expressed in relation to germline editing are concerns for any new technology. Research ethics processes exist to ensure the protection of human participants in such research. There is already a moratorium on, and discouragement of, unsafe research. Beyond safety, no good reasons for restricting germline editing research have been identified. Many accepted technologies are non-therapeutic and have unpredictable effects.

Gene editing is a revolutionary technology, which potentially offers the next generation an enormous range of benefits. It is important that bad arguments, empty rhetoric and personal interests do not cloud rational thinking and deny the next generation the enormous benefits on offer. It is a time for reason, not emotion.

 

[1] Regalado, A. 2015. MIT Tech, Engineering the Perfect Baby http://www.technologyreview.com/featuredstory/535661/engineering-the-perfect-baby/

[2] ibid

[3] Society for Neuroscience. 2004. Early Life Stress harms Mental Function And Immune System in later Years According to New Researchhttp://www.sfn.org/Press-Room/News-Release-Archives/2004/EARLY-LIFE-STRESS-HARMS?returnId=%7B0C16364F-DB22-424A-849A-B7CF6FDCFE35%7D >

[4] Bourne, Douglas and Savulescu (2012). Procreative beneficence and in vitro gametogenesis. Monash Bioethics Review 30(2): 29–48

[5] Marchetti, F., Rowan-Carroll, A., Williams, A., Polyzos, A., Berndt-Weis, M. L., & Yauk, C. L. (2011). Sidestream tobacco smoke is a male germ cell mutagen. Proceedings of the National Academy of Sciences of the United States of America, 108(31), 12811–12814.

[6] Campbell CD, Eichler EE (2013) Properties and rates of germline mutations in humans. Trends in Genetics 29: 575–584

 

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2 Responses to Editing the germline – a time for reason, not emotion

  • Joao Fabiano says:

    Honest question: how can a writing of this quality be published in Nature? I don’t know the Journal politics and policies that well, but I have a two hypotheses, both disturbing. One, they simply do not care about ethics in general and will publish anything writen by autoritive figures outside ethics. Two, they have such a strong pro-conservative bias that they will publish whatever conservative argument they receive. Regardless, I don’t undertand why they don’t think publishing this sort of thing is bad for business by doing reputational damage to the Journal.

  • Paul Knoepfler says:

    I’ve put forth a more operational, specific proposed plan (which I called the ABCD plan) for approaching human germline genetic modification that some of your readers may find of interest:

    It’s over at ipscellDOTcom under ABCD plan.

    Best,
    Paul
    Paul Knoepfler
    UC Davis School of Medicine

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