CRISPR and the Ethics of Human Germline Intervention

By Dr. Priyom Bose, Ph.D.Reviewed by Lauren Hardaker

Genetic modifications in reproductive cells, such as eggs, sperm, or embryos, are commonly referred to as germline editing and are heritable.¹ CRISPR-Cas 9, which stands for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9, is a revolutionary genome editing technology that enables scientists to modify the DNA sequences of human embryos precisely. CRISPR-Cas 9 germline gene editing has raised significant ethical concerns because any unfavourable or unintended genetic changes will be passed on to future generations.²

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CRISPR Germline Gene Editing

Oregon Health & Science University researchers reported the first therapeutic germline intervention using CRISPR/Cas9 in 2017, revealing the potential of this gene editing technique to correct the genetic defect in the zygotes.¹ Since this research was initially intended to assess the feasibility of CRISPR germline gene editing, the genetically engineered embryos were not implanted in utero.

Over the years, researchers highlighted that all germline elements, i.e., oocytes, sperm cells, and embryos, can be edited using CRISPR-based methods.³ For instance, CRISPR can be employed to correct the mutation in the TUBB8 gene that is responsible for developmental arrest after fertilization. Researchers have used CRISPR technology to correct the genetic defect in the retrieved oocyte, and the edited oocyte could be used for in vitro fertilization (IVF). After fertilization through IVF, the embryo can be examined via preimplantation genetic diagnosis (PGD) to explore any off-target effects. PGD helps identify embryos carrying unintended mutations, but does not eliminate specific edited cells within embryos. Embryos with undesirable edits are generally excluded from implantation.

CRISPR has become a therapeutic option for multiple monogenetic diseases, such as β-thalassemia and Huntington’s disease.⁴ Germline editing using CRISPR enables individuals who are carriers of certain hereditary diseases to reproduce without passing on the disease.

Heritable genome editing can potentially prevent the transmission of genetic variants associated with severe genetic conditions and reduce the risk of common polygenic diseases, thereby improving overall health.⁵ Despite the potential advantages of germline editing, particularly as infertility treatment and disease prevention, it is imperative to understand whether genetically edited zygotes could lead to health problems later.

Moreover, broader societal implications, such as unequal access to germline editing technologies and the potential for socio-genetic hierarchies, have entered mainstream bioethical discussions.⁵ The emergence of a “genetic divide” between those who can afford such interventions and those who cannot poses significant equity concerns.

Risks Of Germline Genome Editing on Human Embryos

Germline genome editing on human embryos is associated with severe medical risks, primarily due to off-target effects or genetic mosaicism.⁶ Off-target effects may occur when genomic modification does not occur at target sites. Genetic mosaicism refers to the coexistence of edited and wild-type cells, which can lead to severe health conditions.

Inaccurate or incomplete editing can cause improper translocations, inversions, or large deletions, leading to point mutations. An off-target genetic modification of the human germline risks being passed on to future generations. Therefore, such an anomaly affects one individual and potentially impacts many future generations.

In case of incorrect germline editing, many researchers have also highlighted the potential risk of unwanted modified genes spreading within the human gene pool, with unforeseen consequences.⁷ Also, eliminating pathogenic genes, such as those associated with sickle-cell anaemia, may have unknown positive effects. Furthermore, some modified alleles could interact with other variants in the population in unpredictable ways, posing complex evolutionary risks. The possibility that modified genes could become pathogenic over time raises concerns about the safety of germline gene editing strategies, which could affect an entire population.

Scientists have developed strategies to minimize off-target effects, including optimizing single-guide RNA (sgRNA) design and utilizing high-fidelity Cas9 variants.⁸ Multiple studies have shown that engineered Cas9 variants, such as SpCas9-HF1, eSpCas9, and Hypa-Cas9, increase specificity in gene editing.

Ethical Considerations of Human Germline Intervention

Although CRISPR-Cas therapy has raised hopes in millions of individuals worldwide with severe, and currently incurable hereditary diseases, the potential risk of unwanted mutations in treated cells limits its widespread applications.⁹ Germline editing technology has also sparked ethical and legal debates due to the health risks associated with this technology.  

Considering the ethical perspective of an embryo with off-target effects may pose unknown health risks, many national regulators have banned or restricted human germline intervention. For example, the German legislature has prohibited artificial modification of germline cells. In the US, the National Institutes of Health (NIH) has also decided not to fund clinical studies employing gene editing technologies in human embryos due to unquantifiable safety concerns.¹⁰ However, this does not constitute a blanket federal ban; private entities operating under specific ethical oversight may pursue research, and regulatory discussions remain ongoing.

Scientists argue that off-target risks of human germline therapy do not negate its benefits. They have continually focused on improving the accuracy and specificity of CRISPR/Cas technology. Recent advancements in CRISPR-Cas technology have ensured that unwanted germline modification would not occur accidentally.

Considering the rapid progress in gene editing technology, researchers are optimistic that the current shortcomings of CRISPR germline interventions could be overcome and all uncertainties regarding long-term effects can be minimised to an acceptable level.

The World Health Organization (WHO) is actively developing global standards to regulate and establish a framework for human germline gene editing. The advisory committee involved in this task examines the ethical, scientific, social, and legal challenges associated with human genome editing. It aims to provide guidance and develop international governance mechanisms for human genome editing, which could play a crucial role in developing life-saving interventions. The WHO advisory group’s 2021 and subsequent updates have emphasized transparency, stakeholder engagement, and ethical oversight in response to past controversies, such as the unregulated embryo editing in China 2018.

Broader debates also question the very limits of scientific intervention in human reproduction. Philosophical and bioethical scholars have raised concerns about “playing God,” genetic enhancement, and the manipulation of reproduction.⁵ These considerations continue influencing policymakers and public perception of CRISPR-based embryo modification.

References

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