Gene editing: More genetic disease patients could seek gene therapy by 2030s, say researchers

Key Concepts

• Gene Editing: A technology that allows scientists to make precise changes to DNA.
• CRISPR-Cas9: A specific gene editing technique that uses a guide RNA and a Cas9 protein to snip and replace DNA sequences.
• Genetic Diseases: Diseases caused by abnormalities in an individual's genes or chromosomes.
• Somatic Gene Editing: Gene editing performed on non-reproductive cells, affecting only the individual treated.
• Germline Gene Editing: Gene editing performed on reproductive cells (sperm, eggs) or early embryos, which can be passed down to future generations.
• Bioethics Advisory Committee (BAC): A committee in Singapore that provides guidelines on ethical, social, and legal issues related to biomedical research.
• Primitive Streak: A structure that forms in an early embryo, marking the beginning of cell differentiation and the development of the body's axis.
• Pre-implantation Genetic Testing (PGT): A technique used to screen embryos for genetic defects before implantation during in vitro fertilization (IVF).

Gene Editing Research in Singapore: Advancements and Ethical Considerations

Medical researchers in Singapore are at the forefront of gene editing research, exploring its potential to treat a range of genetic diseases, including heart conditions and blood disorders. The scope of this research extends to potentially treating fetuses in the womb, offering a new avenue of hope for conditions previously considered incurable.

Advancements in Adult Cardiology and Early-Stage Treatments

1. Clinical Trials for Genetic Heart Disease:

• In a significant development for adult cardiology in Singapore, scientists are conducting clinical trials for gene editing to address rare genetic heart diseases. This marks a potential first for commercial use of a gene editing technique on humans in Singapore.
• Impact: Early trial results indicate positive outcomes, with patients experiencing reduced hospital stays, improved mobility, and increased longevity.
• Timeline: Dr. Lynn estimates the trials to be 3 to 4 years from completion, with the possibility of gene editing treatments becoming mainstream by the 2030s.

2. Treating Genetic Diseases at Earlier Life Stages:

• Researchers are also focused on developing methods to safely correct abnormal gene mutations in children and even fetuses before significant disease progression occurs.
• Rationale: Treating individuals at earlier life stages, when they are healthier, is expected to yield better therapeutic outcomes compared to treating those with a substantial disease burden.

3. Patient Consent and Unknowns:

• A crucial aspect of early-stage gene therapy trials is ensuring patients understand that gene therapy is largely irreversible and its long-term side effects are still unknown.

The CRISPR-Cas9 Gene Editing Technique

1. Mechanism of Action:

• CRISPR-Cas9 is a gene editing tool adapted from a natural bacterial defense mechanism against viruses.
• Process:
  • Identification: Scientists pinpoint the specific DNA sequence to be altered.
  • Guidance: A "guide RNA" is designed and attached to a protein called Cas9.
  • Targeting: The guide RNA directs the Cas9 protein to the precise location on the DNA strand.
  • Cutting: The Cas9 protein acts like molecular scissors, snipping out the targeted DNA segment.
  • Repair and Insertion: Simultaneously, scientists introduce a new DNA "blueprint" that the cell uses to repair the strand, allowing for the insertion or replacement of genes.
• Versatility: This technique can be used to target almost any gene, including those responsible for causing diseases.

Ethical Safeguards and Concerns

1. Ethical Hurdles and Guidelines:

• As gene therapy progresses, ensuring robust ethical safeguards is identified as the next significant challenge.
• Bioethics Advisory Committee (BAC) Guidelines: The BAC of Singapore has released new guidelines for the industry, emphasizing caution and the need for assured safety.

2. Controversial Applications:

• Assistant Professor Owen Schaefer from the Center for Biomedical Ethics at the National University of Singapore clarifies that while treating adults and children with gene editing for diseases like heart conditions is not highly controversial, applications involving embryos or gametes (sperm and eggs) are particularly contentious due to their potential for heritability.

3. Concerns Regarding Heritable Gene Editing:

• Unpredictable Long-Term Effects: Altering genes in a way that can be passed down to future generations carries the risk of unforeseen and potentially negative consequences that cannot be accurately predicted.
• Impact on Identity: Editing DNA at the embryonic stage can fundamentally alter an individual's identity, raising profound questions about human nature and being.

4. Caution Despite Potential Benefits:

• While gene editing holds the promise of reducing disease incidence, experts urge caution.
• Alternative Methods: Established methods like pre-implantation genetic testing (PGT) offer safer alternatives for preventing the transmission of genetic diseases.
• Safety and Maturity of Science: Significant safety concerns remain unaddressed, and it is advisable to rely on more certain and safer methods until the science of embryonic gene editing matures.

The 14-Day Embryo Research Rule

1. Historical Context:

• The restriction on developing embryos for research purposes beyond 14 days dates back to the 1970s and the work of the Warnock Committee in the UK.
• Rationale: This rule was established as a compromise, acknowledging ethical objections to altering embryos while recognizing the potential of early embryonic research. At the time, developing embryos past 14 days in a laboratory was not technologically feasible.

2. Scientific Significance of 14 Days:

• At approximately 14 days of development, the primitive streak begins to form, initiating cell differentiation and the establishment of the embryo's body axis. This stage was considered a point where the embryo might be considered more "human-like."

3. Current Relevance:

• Although it is now increasingly feasible to develop embryos past 14 days in a laboratory, the BAC recommends maintaining this restriction.
• Lack of Demonstrated Scientific Value: The committee has not yet seen substantial scientific justification for exceeding the 14-day limit for research purposes.

Conclusion

Singapore is actively engaged in pioneering gene editing research, with promising advancements in treating genetic diseases in adults and exploring early-stage interventions. However, the ethical implications, particularly concerning germline gene editing that can be passed to future generations, necessitate a cautious approach. The BAC's guidelines, including the 14-day restriction on embryo research, reflect a commitment to ensuring that these powerful technologies are developed and applied responsibly, prioritizing safety and ethical considerations alongside scientific progress. The focus remains on leveraging gene editing for therapeutic benefits while carefully navigating the complex ethical landscape.