When we began our project, we were sure we had all the answers right from the start. However, our human practices quickly helped us realize otherwise...

University of Calgary Faculty Presentation

In May 2018, our team held a informational presentation outlining our preliminary ideas and plans for researchers, doctors, and general interest groups at the University of Calgary. We presented a 10 minute pitch of our project, then opened the floor to questions, comments and criticisms from the experts in attendance. Logistical comments were made regarding different transfection methods and whether to use wild type Cas9 or nickase. However, an unexpected yet repeated message from a few experts was to stray away from gene therapy and instead focus on using our toolkit for gene integration. The argument specified that gene therapy is filled with unknowns and hurdles, both physical and ethical, and navigating this landscape would not be worth the effort when our system could be readily applied to any gene integration applications within basic research. The main champion of this viewpoint was Dr. Ian Lewis, a professor at the University of Calgary whom we proceeded to meet with down the road. The specifics of these meetings can be found lower down on this page. This presentation provided us with some tangible laboratory knowledge regarding ideal procedures and methods, however the more salient impact was the effect on our team direction. This faculty session was the first time that we considered pivoting from gene therapy, and instead focusing on developing a gene integration toolkit for broader application in research.

Perhaps the idea of switching gears for our project direction warranted some further investigation...

Safety and Ethical Considerations in Literature Review

With the advice we received from our faculty presentation fresh in our minds, we consulted literature that discussed the safety and ethical considerations attached to gene therapy, CRISPR, and regulation of modified organisms. Even though we planned to make our system as safe as possible, it was important to examine the negative implications that our work could have and the difficulties we might face. Knowing that our project had applications beyond gene therapy and in research as a whole, we delved into related literature with a more critical eye for the pitfalls of a gene therapy-based project.

Through examining present literature, we found out that issues of safety and bioethics are an ongoing discussion, and it is our scientific and moral responsibility to address these discussions due to the implications of our own project. Particularly, we thought it would be beneficial to engage individuals that have backgrounds internal and external to the realm of synthetic biology, whether that be within a laboratory or a public context. These meetings were used to verify preliminary research done on bioethical topics to determine if the surrounding community echoed the sentiment of present literature. In addition, our meetings would inform the framework with which we designed our project.

Meeting with Dr. Ian Lewis

Dr. Lewis works as a Chair for Alberta Innovates: Health Solutions in Translational Health. He also is involved in Metabolomics and is an assistant professor at the University of Calgary. His work centres on connecting metabolic adaptation and virulence of human pathogens, and developing new diagnostic methods and novel antimicrobial therapies. As an interested party, he had attended our faculty presentation earlier in the summer and provided initial thoughts on our project. He was worried about the difficulty of addressing a topic as large as gene therapy, and thought that the sheer amount of unknowns and barriers involved with such an endeavour would prove problematic. He counselled us to use our gene integration framework for generic research purposes.

Now, we met with Dr. Lewis again to talk about our progress and potential applications for our work that might avoid the inherent safety dilemmas within gene therapy. He was particularly interested in our project's applicability as a molecular modification tool, due to its wide usability in several fields of work. He thought the project could be used in molecular biology and gene analysis because it pertains to functions in metabolic disorders (his specialty) in a eukaryotic, human context. Particularly in his lab, work being done on DCMA syndrome (a metabolic disorder) could be advantaged by the use of a tool that allows for the knock-in of genes to characterize their function in the disorder. In a general context he described the potential of Snip, Equip, Flip as an “anvil”, whereas current technology such as CRISPR, could be likened to that of a “sword”. Emphasis put on our project’s utility as a tool for understanding biology further justified a shift toward expanding the scope of our project to become a toolkit for researchers, as opposed to a strict gene therapy system.

Meeting with Dr. Walter Glannon

The team met with Dr. Walter Glannon, a professor of philosophy at the University of Calgary, to discuss ethical considerations related to our project. Dr. Glannon, who specializes in bioethics, provided a unique perspective to the work we performed over the summer. By sticking within the realm of research, he informed us that ethicists would not see many ethical questions as being necessarily relevant.

Due to the nature of our research, we were encouraged to investigate regulatory measures regarding CRISPR and gene therapy, searching for consensus within the research community. While operating within a research context, the use of CRISPR is not constrained. On the contrary, its use as a tool for “knock-outs” (genetic deletions) within a more clinical context raises red flags with ethicists. Gene therapy has struggled to become a widely trusted treatment or cure for genetic diseases, due to past failures, and there are extensive regulations on its use. However, within a conceptual framework, no ethical issues are raised.

Dr. Glannon also encouraged us to look into the source of the cells we worked on for this project. From further investigation, we were able to determine that the HEK293T cells came from a cell line maintained since 1973 from a legally aborted fetus. From Dr. Glannon’s perspective, this is legally, and thus ethically, acceptable, assuming the fetus does not have moral status. This meeting helped us validate that we fully investigated all related ethical considerations within the context of our project.

Dr. Glannon also directed us to a discussion paper on the from the Canada SynBio 2018 Conference that revealed a desire for more transparency in work done within the rapidly evolving field of synthetic biology. This need for openness stems from the reality that society does not always understand research, and therefore fear the unknown. Furthermore, he mentioned the Presidential Commission for the Study of Bioethical Issues, which echoed ideas of transparency with the public, going so far as aiming to implement education programs for the dissemination of scientific knowledge. While bioethics is largely concerned with safety and security issues, it is evident that there is a large movement within bioethical and governmental bodies of power to increase accessibility to synthetic biology and its underlying principles.

The idea of catering our project to general gene integration for research purposes was becoming progressively more appealing. However, we didn't want to give up on gene therapy just yet...

Spiritual Care Advisory Committee Calgary Zone Meeting

The Spiritual Care Advisory Committee members we spoke with consisted of Spiritual Health Practitioners, a family physician, and a community member from various religious denominations including Christianity, Sikhism, Islam and Buddhism. These individuals work closely with families and patients to support in counseling and spiritual well-being, whether it be active listening or the provision of rituals or ceremonies. Furthermore, they provide a conduit between public and spiritual views, while having first-hand experience in patient care.

These thought leaders provided unique, faith-based perspectives on the ideas of genetic modification, biotechnology, and the potential implications of gene therapy. Although it was agreed that therapies which improve the livelihood of humanity are beneficial, there were reservations in the use of a system which could be viewed as altering the natural order. It was evident from our conversation that current society is not wholly prepared for wide-scale use of genetic modification for therapeutic purposes. Specifically, the potential for alterations to the human genome for the sake of enhancement or targeting embryonic modifications were topics that were met with caution. Interestingly, the topic of eradicating defined cultures associated with genetically linked disorders such as deafness or dwarfism was brought up as a negative consequence to gene therapies. Ultimately, it was determined that our team was not equipped to fully counter the negative connotations and safety concerns that accompany the project’s therapeutic applications on a large-scale. As a result, we felt it was apt to limit the scope of our project to an issue shared by both gene therapy and general gene integration within research: reliable gene delivery and activation.

Conclusion

Ultimately, our project direction was swayed by the feedback which we received through our human practices work. While we were initially gung-ho about gene therapy, issues related to safety, ethics, and public viewpoint were brought to our attention which began to dissuade us. Through meetings with research experts, religious thought leaders, the general public, and our own literature review, we came to the conclusion that shifting our project focus to a research-based application was salient. The potential impact of designing a system to address universal problems within gene integration was equally important, but the issues surrounding it were significantly less. Thus, our project pivoted from a gene therapy platform to a gene integration platform for fundamental advancement of biology.

References

Gronvall, G. K. (2015). Mitigating the Risks of Synthetic Biology. Council on Foreign Relations, 1-17.

Inglesby, T.V. and Relman, D.A. (2015). How likely is it that biological agents will be used deliberately to cause widespread harm?. Science and Society, 19(10).

Kinder, J. and Robbins, M. (2018). The Present and Future State of Synthetic Biology in Canada. Institute on Governance, 1-26.

Mulvihill, J. J., Capps, B., Joly, Y., Lysaght, T., Zwart, H. A. E., and Chadwick, R. (2017). Ethical issues of CRISPR technology and gene editing through the lens of solidarity. British Medical Bulletin, 122, 17-29.