Exploring the Ethical Implications of Using CRISPR as a Research Tool to Characterize and Potentially Treat Genetic Disorders

The humane use of animals to help characterize and design treatments for infectious diseases and genetic disorders is a common research strategy. This practice stems from the concept of “animal models,” which is based on the premise that similar conditions that occur in other evolutionarily related species can broaden the investigative scope of the corresponding human illness. Genetic disorders, in particular, make up about 20% of congenital conditions babies suffer from at birth or shortly thereafter. For the past 35 years, University of Portland’s Biology Associate Professor, Dr. Amelia J. Ahern-Rindell has been working on a sheep animal model of a genetic disorder known as GM1 Gangliosidosis to better understand what is going wrong at the molecular, cellular, and organismal levels. It is only when there is a thorough knowledge of the genetic mutation responsible for causing a genetic disorder, that one can hope to correct the condition and ameliorate the pain and suffering of patients.

GM1 gangliosidosis (GM1) is an autosomal recessively inherited lysosomal storage disorder resulting from a decrease in beta-galactosidase activity. Mutations in the GLB1 gene, which codes for beta-galactosidase, is responsible for the disorder and therefore, contributes to the build-up of GM1 ganglioside in the lysosomes of cells. GM1 ganglioside is a component of the neuronal membrane, and thusly its storage leads to severe neurodegeneration. This is a debilitating and fatal genetic disorder that currently is not treatable. As a result, animal models of GM1 are used to learn more about the condition, especially at the molecular level. The research conducted in Dr. Ahern-Rindell’s laboratory on this sheep GM1 variant has shown this ovine model to be similar clinically, genetically, and pathologically to human GM1. Subsequently, she found that this ovine variant has a single base substitution in the GLB1 gene, which may be the mutation responsible for the decrease in beta-galactosidase activity and the accumulation of GM1 ganglioside found in sheep cells and tissues. If the mutation resulting in this ovine GM1 variant can be confirmed, the sheep model can be used for additional research leading to an eventual treatment, or even a cure.

Research conducted currently at the University of Portland’s laboratory by a senior biology major Christina Buselli, utilizes the new gene-editing technology called CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats, to help verify that this suspected base substitution in the GM1-affected sheep is the disorder-causing mutation. Dr. Ahern-Rindell and Buselli are using CRISPR (according to our Institution’s Biosafety Committee guidelines) to introduce edits to the GLB1 gene of unaffected ovine fibroblast cells to reproduce the sequence variation seen in the GM1-affected sheep DNA. Their research goal is to optimize CRISPR editing efficiency in the genetically altered sheep fibroblast cells and then test for a decrease in beta-galactosidase activity. This would provide direct evidence that the base substitution is the causative mutation for this sheep GM1 variant. By utilizing this new CRISPR gene-editing technology coupled with widely practiced cell-culture techniques, Dr. Ahern-Rindell and Buselli hope to make advancements in the study and treatment of the GM1 genetic disorder. However, with this new CRISPR technology comes great responsibility and ethical concerns.

Therefore, Dr. Ahern-Rindell and Buselli applied to the University of Portland’s Dundon-Berchtold Program in the Application of Ethics to also explore the moral use of CRISPR as a gene-editing research tool. The proposed project will help them to conduct scientific research in an ethically acceptable manner and to determine how well-informed the student population is regarding the use of CRISPR to study genetic disorders and its application to treat these fatal conditions. Dr. Ahern-Rindell and Buselli received funding for this academic year as a faculty-student team to design a survey to give to students to assess their knowledge about CRISPR and its use to treat patients with genetic disorders. They received approval from the University of Portland’s Institutional Review Board for the proposed survey and student consent form. Buselli will analyze the survey data and incorporate these findings along with her laboratory research results into her Senior Thesis that she will complete in Spring 2022. She will also give a Seminar Presentation during the University of Portland’s Founders Day celebration in Spring of 2022 when classes are canceled and graduating seniors share their research experiences with the entire campus community. In addition, Buselli will give a presentation at the Dundon-Berchtold Reception in April regarding the CRISPR survey project findings. If possible, Buselli will also attend and present at a national discipline-specific or undergraduate research conference. Hopefully, this senior year of planned activities will make up for the online year Buselli and Dr. Ahern-Rindell persevered through while pursuing the primary literature and coming to better understand the theory behind the methodology they are now employing.

Written by: Amelia Ahern-Rindell and Christina Buselli
Biology Department, University of Portland, Portland, Oregon

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