Heritable human genome editing (HHGE) involves altering the DNA in human embryos, gametes (sperm or eggs), or zygotes (fertilized eggs) in a way that makes these changes inheritable by future generations. This technique is distinct because it does not just affect the individual but also any offspring they might have, potentially altering the human gene pool over time. Read here to learn more.
South Africa recently amended its national health research guidelines, allowing research on heritable human genome editing. This is a significant step, given that most countries strictly regulate or prohibit such practices.
This change, implemented quietly, positions South Africa as the first nation to permit explicit research into creating genetically modified humans, potentially setting a global precedent and sparking ethical and regulatory debates worldwide.
The shift may attract international interest, including research collaborations, but it also raises substantial ethical concerns, particularly regarding the social implications and potential for “scientific tourism” to South Africa for genome editing work
Scientific Background and Techniques
HHGE typically relies on gene-editing technologies like CRISPR-Cas9, TALENs, and zinc-finger nucleases.
- These tools allow scientists to “cut” DNA at specific locations and modify or replace certain genes, theoretically allowing for correction of disease-causing mutations.
- CRISPR-Cas9, for example, has been lauded for its precision and efficiency, although it comes with risks, such as off-target effects (unintended genetic changes) and mosaicism (where not all cells carry the edit).
CRISPR-Cas9
- CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) is the most widely used gene-editing tool today due to its ease, precision, and cost-effectiveness.
- Derived from a bacterial immune system, CRISPR uses a guide RNA (gRNA) to target specific DNA sequences, while the Cas9 enzyme acts as molecular scissors, cutting the DNA at that location.
- This cut can trigger DNA repair processes, which can be harnessed to insert or delete genes, creating targeted modifications.
- CRISPR has broad applications, from curing genetic diseases like sickle cell anaemia to improving crop resilience.
TALENs (Transcription Activator-Like Effector Nucleases)
- TALENs are engineered proteins that can be designed to recognize specific DNA sequences.
- They use transcription activator-like effectors (TALEs), proteins derived from plant pathogens, to bind specific DNA sequences, and nucleases to create double-stranded breaks in DNA.
- TALENs offer high specificity and accuracy, making them effective in gene therapy and agriculture.
- However, they are more time-consuming and costly to create than CRISPR systems, as each TALEN pair must be custom-designed for specific DNA sequences.
Meganucleases
- Meganucleases are naturally occurring enzymes with a high degree of specificity for long DNA sequences (14-40 base pairs).
- Often called “molecular scissors,” they create targeted double-stranded breaks.
- Meganucleases are more specific than other gene-editing tools, but their application is limited because they must match DNA sequences precisely and cannot be easily engineered for new targets.
- However, they are still valuable in areas requiring minimal off-target effects, such as therapeutic applications in human cells.
Zinc-Finger Nucleases (ZFNs)
- Zinc-finger nucleases are engineered proteins combining zinc-finger DNA-binding domains with a nuclease
- Each zinc finger recognizes a specific DNA triplet, allowing researchers to create combinations that target longer DNA sequences.
- ZFNs, similar to TALENs, create double-stranded breaks that enable insertion or deletion.
- They are effective in various applications, including crop genetic engineering and medical research.
- However, like TALENs, ZFNs require complex customization and are often more expensive than CRISPR systems.
Comparison of gene-editing techniques
Tool |
Mechanism |
Advantages |
Limitations |
CRISPR-Cas9 |
RNA-guided DNA targeting, Cas9 creates double-strand breaks |
High precision, easy to use, cost-effective |
Off-target effects, ethical concerns |
TALENs |
TALEs recognize DNA sequences, nucleases cut DNA |
High specificity, fewer off-target effects |
Customizable but costly and labor-intensive |
Meganucleases |
Naturally occurring, cuts specific DNA sequences |
High specificity, minimal off-target |
Limited engineering flexibility |
Zinc-Finger Nucleases |
Zinc fingers recognize DNA, nuclease creates double-strand breaks |
Effective in specific applications |
Complex and costly to engineer for specific targets |
Potential Benefits
- The most often-cited potential benefit of HHGE is the ability to prevent genetic disorders in offspring.
- Diseases like Huntington’s disease, cystic fibrosis, or Tay-Sachs, which are caused by specific genetic mutations, could be eradicated through germline editing.
- It can improve Assisted reproductive technologies such as IVF etc.
- Other advocates propose that HHGE could enhance resistance to infections, reduce the risk of certain cancers, or even extend lifespan.
Ethical and Social Concerns
- Unpredictable Consequences: HHGE carries risks due to our incomplete understanding of genetics, which could result in unintended mutations with long-term effects on health, impacting multiple generations.
- Consent and Autonomy: Altering the human genome of future generations raises issues of consent, as future individuals cannot consent to changes that affect their entire genetic makeup.
- Social Equity and “Designer Babies”: HHGE could lead to social inequality if only wealthy individuals can afford genetic enhancements, raising concerns about a “genetic divide.” The concept of “designer babies,” or genetically enhancing physical, cognitive, or personality traits, raises significant ethical questions about the societal implications of such choices.
- Biodiversity Concerns: Modifying human genetics could reduce genetic diversity, potentially making populations more susceptible to diseases if certain traits become widely edited or preferred.
Current Regulatory Landscape
- Most countries prohibit HHGE for reproductive purposes, including nations within the European Union, the United Kingdom, and the United States.
- Oviedo Convention by European nations prohibits the creation of human embryos.
- International guidelines from organizations like the World Health Organization (WHO) and UNESCO also discourage HHGE for human reproduction until safety, ethical, and social concerns are adequately addressed.
- International Commission on the Clinical Use of Human Germline Genome Editing has been convened by the U.S. National Academy of Medicine, the U.S. National Academy of Sciences, and the U.K.’s Royal Society, with the participation of academies of sciences and medicine from around the world. The commission will develop a framework for scientists, clinicians, and regulatory authorities to consider when assessing potential clinical applications of human germline genome editing, should society conclude that heritable human genome editing applications are acceptable.
- China, however, witnessed controversial cases in 2018 where researcher He Jiankui used CRISPR to edit the genomes of twin girls, sparking global debate and leading to stricter regulations in the country.
- In India, human germline editing and reproductive cloning are banned by the National Guidelines for Stem Cell Research.
Future Directions
- The scientific community generally agrees on the need for a cautious approach, emphasizing extensive research and international collaboration to set ethical guidelines.
- International governance frameworks could provide oversight and ensure that developments in HHGE align with societal values.
- Additionally, experts recommend focusing on non-heritable genetic editing applications, such as somatic cell editing, which affects only the individual being treated and does not pass changes to offspring.
Conclusion
While HHGE holds promise for reducing genetic disease, it is accompanied by significant ethical, social, and scientific challenges. Until more is understood about the potential impacts and until robust ethical frameworks are established, the use of HHGE remains highly restricted and controversial.
The regulatory adjustment by South Africa has drawn mixed reactions. Proponents argue it enables advancements in treating genetic diseases and positions South Africa as a leader in cutting-edge science.
However, critics, including bioethicists, caution that modifying heritable genes could have unintended and far-reaching consequences, both for individuals and society at large.
The move highlights the need for thorough ethical review and alignment with broader international guidelines as the country navigates this complex and contentious scientific territory.
Frequently Asked Questions (FAQs)
Q. How does heritable human genome editing work?
Ans: When genetic changes are made to in vitro early-stage embryos, gametes (eggs and sperm), or germ cells that are the precursors of gametes; genetically modified embryos are then transferred to a uterus to initiate a pregnancy that results in the birth of a child with a modified genome.
Q. What are heritable genetic changes?
Ans: If a parent carries a gene mutation in their egg or sperm, it can pass to their child. These hereditary (or inherited) mutations are in almost every cell of the person’s body throughout their life. Hereditary mutations include cystic fibrosis, haemophilia, and sickle cell disease.
Q. What is the difference between somatic and heritable genome editing?
Human genome editing technologies can be used on somatic cells (non-heritable), germline cells (not for reproduction) and germline cells (for reproduction). Application of somatic human genome editing has already been undertaken, including in vivo editing, to address HIV and sickle-cell disease, for example.
Related articles:
-Article by Swathi Satish
Leave a Reply