Managing the Boundaries of Gene Editing: The Role of Controversies

Blog post by Ella Harvey. See the video here for more information about the origins of the post. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. 

Introduction

CRISPR-Cas9 is a recently developed tool that allows scientists to make precise changes to the DNA sequence in living cells: genome editing, also known as gene editing. In the lab, researchers use CRISPR arrays to target specific sequences of DNA they would like to edit. “Cas9” refers to the enzyme that cuts the cell’s genome at that location. Then, the researchers use the cell’s own DNA repair machinery to introduce or delete bits of genetic material (see figure 1).¹ This technology has become popular because of its relative efficiency, low cost, ease of use and potential to make edits at several sites in the genome in a single procedure.² This system also opens up a whole new realm of medical possibilities, from correcting genetic defects to preventing and treating diseases.³

Figure 1: Guide to CRISPR-Cas9, produced by ‘J LEVIN W’. Reproduced under a Creative Commons Attribution-Share Alike 4.0 International license. Available online at: commons.wikimedia.org/wiki/File:CRISPR-Cas9-biologist.jpg

Though CRISPR-Cas9 possesses massive medical potential, ethical controversy is likely if and when this technology is applied to human germ-line cells, in which much of this proposed medical work would take place. Unlike somatic gene therapy which only affects the recipient’s genome, changes to germ-line genetic material may be passed on to future generations.⁴ Thus, germ-line application of CRISPR-Cas9 connects the technology with long standing social, religious and historical controversies related to the question of who has the authority to make decisions about human evolution.5 Concerns include the creation of “designer babies” at the behest of parents using genome editing to select for desirable traits in their progeny.

Though the great majority of genome editing research does not take place in viable human germ-line cells, the controversy that a premature application of this technology in viable zygotes (fertilised eggs) would unleash threatens to destabilise the entire field by making the use of CRISPR-Cas9 taboo. Preventing these public controversies from emerging is important to all proponents of genome editing research, regardless of their research’s clinical or pre-clinical, somatic or germ-line setting, because societal and ethical debates may influence the direction of funding flows and shape national research agendas.⁵

In the following discussion, I show how leading gene editing scientists constructed a standardised methodology for the usage of CRISPR-Cas9 technology in germ-line cells through a 2017 National Academies of Science Report in an attempt to stabilise the gene editing research network following a shocking advance in 2015. Then, I show how this elite response to a 2018 experiment by He Jiankui took advantage of that controversy to cement these rules. Finally, I show how the rest of the scientific community fell into line in the controversy’s aftermath, demonstrating that the elites effectively stabilised the gene editing research network.

 

Construction of a Standardised Methodology for the Use of CRISPR-Cas9 Technology in Human Germ-Line Cells

The seeds of controversy surrounding the use of CRISPR-Cas9 technology to genetically alter human germ-line cells were planted in April 2015 when a Chinese team became the first to effect genetic changes in human embryos. In a paper published on April 18^th in the Protein and Cell journal, Junjiu Huang and his colleagues at Sun Yat-Sen University described how they attempted to use the CRISPR-Cas9 system to edit the human beta-globin gene, the gene associated with the blood disorder beta thalassemia, in 86 human embryos. Huang’s team only used unviable zygotes in an attempt to achieve success without sparking controversy that would follow allowing the modified zygote to develop to term.⁶

This study was a monumental progression in human genetic modification research. However, it was also a frightening step towards shrouding well-intentioned gene editing research in controversy. As a result of these fears, an ad hoc group of scientists called for a global moratorium on human germ-line gene-editing in 2015 to allow themselves time to set up a new infrastructure to regulate the future use of CRISPR-Cas9 in viable human zygotes.³

The first International Summit on Human Gene Editing was called that December in Washington, D.C. to give the leaders of the gene editing research community a stage to publicly define the approved uses of CRISPR-Cas9 in viable human zygotes. This summit was co-hosted by the USA’s National Academy of Sciences and National Academy of Medicine, the Chinese Academy of Sciences and the UK’s Royal Society. Only the most respected voices in the human gene editing field were invited. The decisions produced by this group would set parameters for the future use of CRISPR-Cas9 in human germ-line cells. Therefore, through this conference, the power to police the the usage of this gene editing technology in the human germ-line was placed in the hands of international scientific research elites.⁷

The Summit’s conclusions were formalised in the 2017 National Academies of Science Report. According to the report, heritable germ-line editing can only be used in the absence of reasonable alternatives for the prevention of serious diseases on genes that have been convincingly demonstrated to cause or strongly predispose individuals to that disease or condition. Before a study, thorough pre-clinical trials must be performed to understand the risks and potential health benefits of the procedure. The health and safety of the research participants must receive rigorous oversight during and after the trial. The guidelines also emphasised the importance of practicing maximum transparency to allow oversight mechanisms to work and prevent the usage of human gene editing in inappropriate circumstances.⁸

With these guidelines as a framework, the gene editing research elites invited stricter government regulation of their field to prevent the premature application of the CRISPR-Cas9 technology to viable human germ-line cells that threatened to mire their pre-clinical gene editing research in controversy. Theoretically, if everyone abided by these rules, everyone would be able to work towards their individual objectives and contribute to the development of knowledge without infringing on the progress of other scientists.

 

The Breaking and Defending of the Boundary From Violators: The Case of He Jiankui

The boundaries set by the gene editing elites were put to the test when the Southern University of Science and Technology (in Shenzhen) scientist He Jiankui proudly announced through a self-published YouTube video on November 25^th 2018,⁹ that he had created the world’s first genetically edited babies, using CRISPR-Cas9 to make twins resistant to their parent’s HIV.¹⁰

He would not receive the congratulatory response from the scientific community he expected because his methodology violated nearly every important tenet of the guidelines put forward in the 2017 National Academies of Science Report. First, on the most basic level, He’s goal to make the babies resistant to HIV, a treatable condition, did not meet the threshold of addressing a “serious, unmet medical need” that would justify embryo editing.¹¹ Secondly, the secrecy surrounding He’s experiment violated the Report’s “maximum transparency” clause on several fronts. He had funded the experiment himself, which allowed him to perform the study largely in secret.¹⁰ Seemingly to keep his study under wraps, He stalled for months before listing the experiment on the official Chinese registry of clinical trials.¹¹ Even after He announced Lulu and Nana’s birth, He did not provide peer-reviewed data about his research and methods.¹² As a result, even the Southern University of Science and Technology was unaware of He’s study.10 Third, his decision to go ahead and implant an edited embryo regardless of the off-target genetic mutations he found in many zygotes, and the widely held view in the gene editing field that the CRISPR-Cas9 technology was not ready for clinical human application, indicated he did not fully understand the “kaleidoscope of unforeseeable health risks for the twins and their progeny” posed by his procedure.³

He Jiankui’s actions represented a bold public violation of the boundaries constructed by the gene editing research community elite but, it also provided the leading voices in the field with an opportunity to fortify these boundaries in their public rejection of He’s work at the Second International Human Genome Summit where he was scheduled to speak. This summit, that ran from 27-29^th November 2018, brought together a wide range of human gene-editing stakeholders including researchers, ethicists, policymakers, patient groups and representatives from science and medical academies and organisations worldwide.⁷ Thus, the conference presented the gene-editing elites with a perfect audience to demonstrate their commitment to policing the boundaries of the legitimate usage of CRISPR-Cas9 technology in human germ-line cells.

From the transcript of He’s session at the Summit, it is clear the conversation’s moderators, Robin Lovell-Badge and Matt Proteus, acted to represented the interests of the gene-editing elites by using leading questions to communicate that He’s trespassing of the boundaries set forth in the 2017 Report made his results illegitimate in the eyes of the field’s leading figures. He Jiankui was the final speaker of five in the “Human Embryo Editing” section of the Summit. Originally, the five speakers were meant share a single Q&A session following their presentations.¹³ However, after He’s bombshell announcement just two days before the conference, the Summit’s organisers altered the schedule so that He would have a separate Q&A session to allow the moderators and audience members a chance to fully engage with the biophysicist in his first (and only) public talk about his experiment.¹⁴

Figure 2 – He Jiankui speaking at the Second International Human Genome Summit, November 2018. Public domain image taken from: https://commons.wikimedia.org/wiki/File:He_Jiankui_at_Summit_on_Human_Genome_Editing,_Hong_Kong.png

In front of more than 160 press representatives squeezed into one section of the auditorium, it would be up to the conference’s moderators to condemn He’s actions, absolve the human gene editing research leaders of blame and defend the boundaries of the 2017 Report’s regulatory framework. After He’s slide presentation of his data, he took a seat in centre stage for, essentially, a targeted interrogation by Lovell-Badge and Proteus that highlighted how He’s methods violated the approved methodology for human genome editing research at every step, thinly veiled as a polite “panel discussion.”¹⁵ For example, the moderator asked, “Why did you choose CCR5 when there are established ways of avoiding HIV transmission during conception?” Here, the moderator’s confrontational tone communicates the gene-editing elites’ rejection of He’s transgression of the 2017 Report’s “absence of reasonable alternatives” clause. The moderator went on to ask “Why did you ignore the salient view of the scientific community that treatment would be premature and irresponsible without a consensus on its acceptability?”¹⁶ In this way, the moderator served to erect the standard methodology as a boundary between He and the rest of the rule-abiding scientific community, attempting to prevent their own legitimate uses of the CRISPR-CAs9 technology from being tainted by He’s reckless application.

To the rest of the gene-editing research community, He’s public rejection by the gene-editing elites served as a warning. Any other researcher that dares to cross the boundaries constructed by the 2017 Report can expect to meet the same fate as He: a loss of legitimacy in the eyes of the field’s elites that hold great sway in the discourse and thus, the funding flows surrounding gene-editing research.

 

Acceptance of Boundaries: Responses to He Jiankui’s Work

A new level of international recognition of the boundary constructed in the 2017 Report following the Second International Human Genome Summit was demonstrated by the wide range of gene-editing researchers that hurried to release their own critical statements on He’s work in the days following the conference to prove that they fell on the right side of the boundary. This dynamic was especially salient in research institutions that He implicated in supporting his 2018 experiment. For example, He claimed that Michael Deem, a professor of biochemical engineering at Rice University, knew about the project. Rice University was quick to proclaim that it had no knowledge of He’s work and that it had launched a “full investigation” into Professor Deem.3 The Southern University of Science and Technology also stated that they were unaware of the project and had launched their own investigation into He’s lab.¹⁷

 

Concluding Remarks

From this discussion, we learn that sometimes controversy is necessary for the establishment of stability. He Jiankui’s use of CRISPR-Cas9 to produce two genetically-edited babies may have been exactly what the gene editing elite were trying to avoid through the standard methodology set forth in the 2017 National Academies of Science Report. However, Lulu and Nana’s existence demonstrates that these rules were toothless before He Jiankui’s strategic ostracism on the world stage by the powerful gene editing elites. Instead of allowing public perception to indict the entire CRISPR-Cas9-wielding network with unethical behavior, the elites took the controversy by the reigns. It was a textbook execution of Thomas Gieryn’s theory of boundary work in which scientists attempting to establish intellectual authority in a field dole out scientific legitimacy to those that abide by their constructed boundary and mark those who do not as “outsiders.”¹⁸ Only after He’s interrogation on the world stage at the Second International Human Genome Summit illustrated the consequences of trespassing the boundary set forth in the 2017 Report did the international gene editing network finally recognise the authority of the elite’s rule of law.

 

References

1. “What are Genome Editing and CRISPR-Cas9?”
2. “Editing human embryos ‘morally permissible’”
3. Shanley Pierce, “Scientific experts respond to Chinese scientist’s claims of creating world’s first gene-edited babies”
4. Nikolas H. Evitt et al., “Human Germline CRISPR-Cas Modification: Toward a Regulatory Framework”, The American Journal of Bioethics.
5. Barbara Prainsack et al., “Stem Cell Controversies 1998-2008: Controversies and Silences”, Science as Culture.
6. Jocelyn Kaiser and Dennis Normile, “Embryo engineering study splits scientific community”
7. National Academies of Sciences, Engineering and Medicine, “International Summit on Human Gene Engineering”
8. National Academy of Sciences and National Academy of Medicine, “Human Genome Editing Science, Ethics, and Governance: Report Highlights” 
9. He Jiankui’s YouTube announcement: https://youtu.be/th0vnOmFltc.
10. “He Jiankui: China condemns ‘baby gene editing’ scientist”
11. Sharon Begley and Andrew Joseph, “The CRISPR shocker: How genome-editing scientist He Jiankui rose from obscurity to stun the world”
12. Lisa M. Krieger, “Scientist at center of gene-editing controversy worked at Stanford”
13. http://www.nationalacademies.org/cs/groups/genesite/documents/webpage/gene_188526.pdf
14. https://dev.biologists.org/content/develop/146/3/dev175778.full.pdf
15. A recording of He Jiankui’s session at the Summit can be reached at this link: https://youtu.be/tLZufCrjrN0.
16. Peter Mills, editor, “What He Said”, Nuffield Council on Bioethics.
17. Michelle Roberts, “China baby gene editing claim ‘dubious’”
18. Thomas F. Gieryn, “Boundary-Work and the Demarcation of Science from Non-Science: Strains and Interests in Professional Ideologies of Scientists”, American Sociological Review.

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