A Case of Non-Human Gene Editing
InstructionsA Case of Non-Human Gene Editing
The aim of this module is to facilitate reflection upon the ethics issues associated with the development and use of non-human gene editing in a research project.
Learning outcomes
At the end of this module, learners will be able to:
- Identify and analyse the ethics issues and dilemmas associated with an example research proposal.
- Make suggestions for how the ethics issues might be addressed.
- Identify ethics guidelines and policies that are relevant to the proposed research.
About Malaria
Malaria is a life-threatening disease caused by Plasmodium parasites that are transmitted to humans through the bites of infected female Anopheles mosquitoes. Once inside the human body, the parasites travel to the liver, where they mature and multiply before entering the bloodstream, infecting red blood cells. This leads to symptoms that can range from mild to severe, and without timely treatment, malaria can cause serious complications and even death. Common symptoms of malaria include fever, chills, headache, muscle aches, fatigue, nausea, and vomiting. In severe cases, malaria can cause anaemia, respiratory distress, cerebral malaria (affecting the brain), organ failure, and death if left untreated.
The Research Proposal: MoMotEM
Perspectives: A Malaria Zone Resident
Modified Mosquito Poll
Keeping this perspective in mind, answer the question below. Do you want the modified mosquitoes to be released?
Feedback
Of course, this is a difficult decision to make without full information about the potential risks and benefits of the study. Having heard about what it is like to live with the constant fear of malaria infection, the primary benefits should be obvious. But are they enough to outweigh the potential risks? On the next page, we start to consider some of those risks.Perspectives: An Ecologist
The ecologist’s perspective
As an ecologist, I have serious concerns about the proposal to use gene drive technology to eradicate malaria-carrying mosquitoes. While the goal of eliminating malaria is undeniably important, the potential risks to ecosystems, biodiversity, and the natural world need to be carefully considered before taking such a drastic step.
One of my main concerns is biodiversity disruption. Mosquitoes are not just pests; they play important roles in ecosystems. For example, male mosquitoes are pollinators for some plants, and many species of birds, fish, and bats rely on mosquitoes as a food source. If we wipe out a mosquito species, we could disrupt food chains in ways we can’t fully predict. Ecosystems are incredibly complex and fragile, so the extinction of one species can lead to a chain reaction, potentially causing other species to disappear. In regions that are already struggling with food security, this kind of disruption could lead to further ecological damage and even food shortages. The consequences could be devastating for both nature and the people who rely on it.
Then there’s the issue of gene flow to non-target species. In the wild, mosquitoes sometimes interbreed with closely related species. There’s a real risk that the gene drive could spread to non-target mosquitoes, including those that don’t carry malaria. If that happens, we could see a dramatic drop in mosquito populations beyond what’s intended, affecting species that depend on them for food or pollination. Imagine what would happen if all mosquito species suddenly disappeared—we’re talking about a potential collapse of ecosystems that rely on them, creating ripple effects throughout the environment.
And let’s not forget about ecosystem irreversibility. Once these gene drives are released into the wild, they’re self-propagating, meaning they spread on their own. If something goes wrong, there’s no way to take it back. We can’t hit an “undo” button on nature. This kind of irreversible interference with ecosystems raises ethical questions about how much we should be tampering with the natural world. We could be altering the balance of mosquito populations forever, and that’s a weighty decision to make.
What do you think?
What do you think? It’s clear that this ecologist would not want the study to go ahead. In your role as a member of a research ethics committee, do the concerns the ecologist has raised convince you that the study should not proceed?
Feedback
Exploring Potential Risks and Benefits
Risks and Benefits: Delving Deeper
The identification of potential benefits and risks is necessary but is not sufficient for ethics assessment. In order to weigh the benefits and risks, we also need more information about who will benefit and how, as well as the steps that will be taken to avoid and/or mitigate the risks.
Who benefits from the research?
While we hope that, ultimately, this research will benefit populations around the world where malaria is endemic, the companies or research institutions developing gene drive technology might benefit more financially than the local population where this study will take place. This raises important ethical questions about equity, justice, and the distribution of benefits.
They are also likely to have more influence over the direction and application of the research, particularly if they control the intellectual property rights. This creates an inherent power imbalance, where local populations rely on external actors to solve a local problem. If the technology becomes commercialized, the local communities might not even be able to afford to use it, or conduct the necessary post-study monitoring, even though they are the ones facing the direct impact of malaria and are taking the risks by acting as a test site for the intervention.
Without proper engagement and consent, this could be seen as exploiting vulnerable populations for scientific experimentation and commercial gain. To avoid exploitation, it is critical that local populations are not simply a test case for technology that will later profit wealthy institutions elsewhere. Careful and inclusive planning, with clear contracts and ethical agreements can help prevent exploitation and ensure that the local population’s needs and interests are prioritised.
Ensuring transparent governance and local decision-making power is essential. Local communities and governments should have a strong say in how the gene drive is developed and deployed. This can include setting up oversight committees that involve representatives from the local population, NGOs, and international experts, so that decisions about the gene drive’s use prioritise community interests and ethical concerns.
Additionally, long-term sustainability plans should be developed to ensure that local populations are not dependent on foreign manufacturers or researchers for their ongoing health needs. Building local capacities to monitor and maintain the gene drive populations could ensure that the benefits continue without external oversight, empowering communities to control their own health futures.
The Governance of Gene Editing Research Involving Gene Drives
Releasing gene drive organisms into the environment could have transboundary impacts, and neighbouring countries or regions that are not part of the trial could be affected. This raises questions about who should regulate gene drives, how decisions should be made, and how to resolve conflicts between nations or regions with differing views on the technology.
A Checklist for Research Ethics Committees
This checklist is intended for use as a supplement to the usual ethics review process regarding matters that are mainly specific to the use of gene drive technology in research. All usual aspects of research ethics review will also need to be considered, for instance, compliance with national and international regulations and the appropriate health and safety measures. Additionally, the checklist is not exhaustive; there may be other issues pertaining to individual studies that are not included here. Nevertheless, alongside general guidelines and processes, it provides a useful starting point for ethics reviewers.
Environmental impacts
- Do the project activities risk ecosystem disruption?
- Has a thorough environmental impact assessment has been conducted, including for the potential effects on biodiversity, ecosystems, and food chains?
- If yes, what does this tell us?
- If no, are there plans to conduct this before any release of the gene drive?
- Do the researchers have a reasonable plan to monitor and manage unintended ecological consequences?
- How have the researchers taken account of the possibility of irreversible ecological changes?
- What safeguards are in place to protect biodiversity?
- Have the researchers paid due attention to the broader, global implications of releasing the gene drive?
- How will the technology be responsibly managed if it extends beyond the target regions?
Human health and wellbeing
- Are there risks to human health and wellbeing?
- If so, are appropriate measures in place to minimise harm to local populations (e.g., healthcare support, disease monitoring).
- Are appropriate measures in place for delivering health benefits to the local populations?
- Is there an appropriate plan for long-term monitoring of human health impacts?
Technological and other risks
- Do the researchers have an appropriate plan to monitor and manage unintended evolutionary consequences?
- Have the risks of gene flow to non-target species (e.g., through hybridization) been properly assessed and are appropriate precautions are in place?
- Is there an appropriate strategy to monitor and respond to evolutionary resistance, including adjustments to the gene drive or alternative interventions if resistance develops?
- Do the researchers have an appropriate contingency plan for halting or reversing the gene drive if negative effects are observed (for instance, gene drive off switches, or self-limiting mechanisms)?
Community involvement
- Have the local community been meaningfully involved in decision-making processes related to the project design and implementation?
- How is the consent process being managed?
- How will it be ensured that all those affected (including individuals, groups, and local leaders) understand the potential risks and benefits fully?
- How is the option to opt out of the study managed?
Equity
- Is the research to be situated in a low or lower-middle income country?
- If so, how are the researchers taking steps to avoid ethics dumping?
- Who are the potential beneficiaries of this study?
- Will the resultant benefits be accessible to the local populations?
- Has a plan for equitable sharing of the benefits arising from the research been agreed with the local communities?
- Will the local population have the capacity and resources to manage and monitor the technology after the research phase concludes, ensuring local control over future developments?
Study justification
- Is there a justifiable need for this study?
- Might the same objectives be achieved via less risky and/or less costly methods?
Would you Approve the Study?
Now it is time to decide whether or not to approve the study. As a member of the research ethics committee, which option will you go for?
Feedback
Module Evaluation
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Thank you!Glossary
Allele: One of two or more versions of a gene. Organisms inherit one allele from each parent for every gene. Different alleles can produce variations in traits, such as eye colour or disease susceptibility.
Cas9 (CRISPR-associated protein 9): An enzyme that acts like molecular scissors, capable of cutting DNA at a specific location, allowing for targeted gene edits.
CRISPR-Cas9: A gene-editing tool that uses a protein called Cas9 and a guide RNA to cut DNA at specific locations, allowing for targeted modifications.
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats): A sequence of DNA found in the genomes of bacteria and archaea that provides a genetic record of viral infections, used as the basis for gene editing technology.
Dominant trait: A trait that is expressed when at least one copy of the dominant allele is present.
Ex vivo editing: A gene-editing technique where cells are modified outside the body (in a lab) and then reintroduced into the patient.
Gene: A segment of DNA that contains the instructions for producing a specific protein or trait.
Gene drive: A genetic mechanism that increases the likelihood of a particular gene being inherited by offspring, often used to spread specific traits through a population.
Gene editing: The process of making precise changes to the DNA of an organism, either by adding, deleting, or altering genetic material.
Genome: The complete set of genetic material (DNA) in an organism, including all its genes.
Genotype: The genetic constitution of an organism, referring to the specific alleles an individual carries.
Gene therapy: A medical approach that involves altering genes within a patient's cells to treat or prevent disease, often using tools like CRISPR-Cas9.
Germline editing: Gene editing of reproductive cells or embryos, resulting in changes that can be passed on to future generations.
Guide RNA (gRNA): A short RNA sequence that directs the Cas9 enzyme to the specific part of the genome that needs editing by matching its complementary DNA sequence.
Horizontal gene transfer: The movement of genetic material between organisms in a manner other than traditional reproduction.
In vivo editing: A gene-editing technique where the CRISPR-Cas9 system is delivered directly into the body to modify cells within the patient.
Knock-in: A genetic modification where new genetic material is inserted into a specific location in the genome using CRISPR-Cas9.
Knockout: A genetic modification where a specific gene is completely inactivated or "knocked out" to study its function or disable a harmful gene.
Mendelian Genetics: The branch of genetics that studies how traits are inherited according to the principles discovered by Gregor Mendel through his work on pea plants.
Mosaicism: If not all cells may receive the intended modification, this can lead to mosaicism whereby some cells carry the edited gene, while others do not. This is more commons when gene editing is done at the embryonic stage or in early development.
Mutation: A change in the DNA sequence of a gene, which can alter the function of the gene or result in a new trait.
Off-target effects: Unintended modifications made by CRISPR-Cas9 at sites other than the intended target, which can result in unwanted mutations.
On-target effects: Even at the intended target site, gene editing can result in unintended changes. For example, small insertions or deletions that can alter the function of nearby genes or regulatory elements.
Phenotype: The observable characteristics or traits of an organism, which are determined by its genetic makeup (genotype) and environmental factors.
Recessive trait: A trait that is expressed only when two copies of the recessive allele are present.
Somatic cells: All cells in the body except for sperm and egg cells. Somatic cell gene editing: Gene editing performed on somatic (non-reproductive) cells, affecting only the individual and not their offspring.
Targeted mutation: A deliberate alteration in a specific gene sequence to study gene function or produce a desired trait.References
Genome editing: and ethical review, Nuffield Council on Bioethics 2016, Available at: https://www.nuffieldbioethics.org/assets/pdfs/Genome-editing-an-ethical…
How gene drive works, Target Malaria, available at: https://targetmalaria.org/what-we-do/how-it-works/
Garrood WT, Cuber P, Willis K, Bernardini F, Page NM, Haghighat-Khah RE (2022) Driving down malaria transmission with engineered gene drives. Frontiers in Genetics, 19(13) :891218. Available at: https://www.frontiersin.org/articles/10.3389/fgene.2022.891218/full
Hartley S, Smith RDJ, Kokotovich A et al. (2021) Ugandan stakeholder hopes and concerns about gene drive mosquitoes for malaria control: new directions for gene drive risk governance, Malar J 20: 149. https://doi.org/10.1186/s12936-021-03682-6
Nolan, T (2021) Control of malaria-transmitting mosquitoes using gene drives, Phil. Trans. R. Soc. B37620190803 http://doi.org/10.1098/rstb.2019.0803
Saey, TH (2022) Who decides whether to use gene drives against malaria-carrying mosquitoes?, Science News, available at: https://www.sciencenews.org/article/gene-drives-mosquito-malaria-crispr…
