Ethics for CRISPR and the Big Leap Forward

By Kelsey Berry

This week, a research group in China published a paper describing a significant step forward in one application of the genome editing technique CRISPR: they used it to modify the genome of non-viable human embryos. Now, the scientific community finds itself grasping for ethical and legal foundations in order to evaluate the implications of this work and its possible extensions. Bioethicists and philosophers have been laying these foundations for years. Yet, the key problem, as always, is in translation: as we shift from science fiction to scientific reality, the robust and rigorous literature on the ethics of human population enhancement must find its way to usefully inform the policy debate and scientific practice. Translation between these camps can be thorny, but it must start with convergence on the issues at stake. Here’s a quick primer on the issue:

The spark: A team out of Sun Yat-sen University in Guangzhou led by Junjiu Huang used the CRISPR technique in non-viable human embryos to modify the gene responsible for a potentially fatal blood disorder. Leading journals Science and Nature denied the group publication on ethical grounds; the paper can be found in Protein & Cell. This is the first time that the CRISPR technique has been used to modify the human germline; however, the team specifically selected non-viable embryos in which to conduct the experiment in order to side step some of the most pressing ethical concerns.

The technology: CRISPR, which stands for “clustered regularly interspaced short palindromic repeats” refers to DNA loci that contain repeated base sequences, separated by other sequences called spacers. These spacers are like memories from previous exposure to a virus, and they tell the biological system which invaders to look out for and destroy – a key part of an adaptive immune system. In 2012, a team led by Doudna and Charpentier showed that CRISPRs could also be used to zero in on DNA sequences of their choosing simply by introducing synthetic guide RNA that matched the DNA sequence they wished to target. The CRISPR system would then slice up the targeted DNA sequence, either knocking out a gene entirely or allowing researchers to insert a “patch,” which if incorporated into the DNA sequence would modify the target gene. Since 2012 this technique has been shown to work in several organisms, including in human cells.

Applications: Genetic modifications that used to require careful crossbreeding through generations or, with more recent techniques, months and years of careful protein development, now takes only days or weeks with CRISPR. The ease and precision possible with the technology has revolutionized gene editing, opening up seemingly endless possibilities. The technique has already been used to modify human somatic cells (where changes are not passed on to future generations) as well as animal embryonic cells (where changes are passed on to future generations). Chief health applications include therapeutic modifications to human somatic cells in order to correct defective genes and potentially reverse the course of a genetic disease like cystic fibrosis or sickle-cell anemia. If used to modify human embryonic cells in viable embryos, the technique could prevent the development of such genetic mutations not only in the embryo and resultant organism itself, but in all descendants of that organism.

Ethical concerns: First, and most simply, the technique is still in its infancy. Despite its allure, its safety and efficacy are still being sussed out, making it it unready for clinical application. Results from the Huang team confirmed the difficulties of using the technique to create an embryo with (1) a perfectly altered target gene and (2) no hitchhiking genetic mutations that might result in unintended and potentially harmful effects. Of the embryos used, 80% survived; only 52% of those were successfully cleaved by CRISPR/Cas9, and only 14% of those contained the replacement genetic material. In the others, imprecise editing created a “genetic mosaic.” Off-target mutations inadvertently damaged other DNA sequences in all cleaved embryos.

However, finding the right mix of health benefits and risks for this new technology does not exhaust the debate. Once perfected, the technique promises the capability to edit the germline with astonishing ease, and these changes to the germline extend to future generations. Aside from the typical ethical concerns relating to justice (including concerns about access and resource allocation) and consent (including standards for informed, voluntary use) in the wake of a new medical technology, modification of the germline also implicates a heated debate about the conservation of nature – in this case, human nature. The capacity to eradicate particular genetic diseases is staggering in its implications; the further capacity to selectively modify certain traits for other life-enhancing reasons (for instance, cosmetic or to expand an average capability-set) gives pause to many. These are the topics up for debate as we navigate the CRISPR terrain.

Legal background: A 2014 survey of the international regulatory landscape found that 29 of 39 countries examined had bans on human germline modification based on law or guidelines. This does not include the US, which currently does not ban human germline modification, but has taken a “restrictive” posture toward it via NIH guidelines. Any clinical application would likely be regulated by the FDA.

The way forward: In March 2015, a group of leading American biologists, led by Jennifer Doudna, one of the inventors of CRISPR technology, published a paper in Science calling for a moratorium on doing such work for clinical purposes, citing concerns about safety, efficacy, and the broader ethical landscape. Others have called for a halt on the research into germline modification in order to insulate research on somatic cell modification from possible backlash. However, these pieces strike me as alarmist and dependent on tenuous arguments, as they brazenly commit the slippery slope fallacy rather than giving voice to the rigorously argued ethical claims about human modification and the possible benefits of refining the technology. Ideally, the debate will proceed in a more rigorous fashion and not prematurely condemn all research on this important technology. However, this will require a concerted effort to translate concepts, considerations, and claims between ethicists, biologists, and policy makers — a discourse I hope to contribute to.

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One thought on “Ethics for CRISPR and the Big Leap Forward

  1. All this action and controversy indicates the profound significance of crispr. Has there ever been a profound discovery that wasn’t accompanied by the “Two-Headed Serpent”?

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