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【 胡務亮 Paul Wuh-Liang Hwu 】【 李崇僖 Lee Chung-Hsi 】

2025/07/16
Dr. Paul Wuh-Liang Hwu

Professor, College of Medicine, Pediatrics, National Taiwan University, Taipei, Taiwan / Distinguished Research Fellow, China Medical University Hospital, Taichung, Taiwan.

In this week’s New England Journal of Medicine, two research articles published by groups of researchers from the UK describe the success of mitochondrial donation treatments for mitochondrial DNA (mtDNA) diseases.

Each human cell contains a few hundred mitochondria. The mitochondrion is a double membrane-bound organelle, and each mitochondrion contains a few copies of double-stranded, circular DNA molecules of around 16,500 genetic units (base pairs). Mitochondria are responsible for energy (ATP) production, fatty acid oxidation, and some other functions for the cells. Pathological variations or deletions of mitochondrial DNA can impair mitochondrial function, and when the proportion of defective mitochondria (heteroplasmy level) is high, cause serious symptoms involving the brain, muscle, and metabolism. During reproduction, all mitochondria are inherited from the mother (the egg). However, the level of defected mitochondria in offspring can be very different from their mothers, leaving reproduction planning almost impossible.

In the two studies, mitochondrial donation by pronuclear transfer (PNT) was conducted to reduce the reproductive risk of women with mitochondrial diseases. Both the mitochondrial donor and patient eggs were fertilized first.

The nucleus of the donor's fertilised egg was removed and discarded, leaving behind a fertilised egg without a nucleus but with healthy mitochondria. The nucleus from the patient’s fertilised egg was then transferred into this enucleated donor egg. The PNT zygote was then cultured and implanted to continue pregnancy. All live births were in good health and with low levels of defective mitochondria.

PNT has been widely used in animal research and now proved to be safe and efficient in humans. This breakthrough gives a reproductive choice for women affected with mitochondrial diseases, which is very important for the patients and their families. However, this study also broke the ban for continuing pregnancy of genetically manipulated human embryos. One argument is that PNT does not really touch the genetic materials but only provides normal mitochondria. The excellent outcome of this study also eases the concerns of nuclear/mitochondrial genome compatibility and other safety issues.

Nevertheless, one may still worry if this technology will be abused to improve human physiological quality, for example, creating a body with more efficient energy production. Then, how about adding a little bit of normal, or good, DNA to the nuclear genome, if we can do that safely? Pronuclear transfer was meant to treat genetic diseases, but it could be misused.

As doctors and researchers who take care of patients with genetic disease, we welcome inventions, including reproduction medicine, that can help patients. Certainly, before the safety of new treatments can be confirmed, they should be used in patients with no other choices, or with a favorable benefit over risk.

Recently, gene therapies, including gene editing treatments, are rapidly developing, offering hope to patients who previously have no option for treatment. However, we need to ask people to restrain themselves, not to apply PNT or gene therapy to improve the health of people without a medical condition, but to let these new treatments be developed to rescue lives of patients.

Declared of interests: None.

2025/07/16
Lee Chung-Hsi 

Professor, Graduate Institute of Health and Biotechnology Law, Taipei Medical University, Taipei, Taiwan.

Pronuclear Transfer Technology: Advancing with Cautious Innovation and International Consensus

While early clinical results show promise in reducing the level of pathogenic mitochondrial DNA in newborns, the application of Pronuclear transfer (PNT) raises significant ethical and regulatory questions that must be addressed through both national oversight and international dialogue. From a bioethical standpoint, germline modification—defined as altering genetic material in a way that affects future generations—has long been met with caution. This is because it involves irreversible changes to the human genome, with potential consequences not only for the individuals born from such interventions but also for society’s understanding of what it means to be human.

Pronuclear transfer, however, occupies a unique space in this debate. It targets mitochondrial DNA, which, although essential for cellular energy production, contributes relatively little to traits traditionally associated with identity, such as physical appearance, personality, or intelligence. Because of this limited influence on key phenotypic characteristics, PNT is viewed by some as an acceptable “ethical testing ground” for germline-level intervention. Rather than resorting to high-risk gene therapy after the onset of a hereditary disease, using PNT technology to reduce the likelihood of disease is a more ethically acceptable option. It provides a possible pathway to explore the responsible use of reproductive technologies without crossing the bright-line boundaries typically drawn around nuclear DNA modification.

Nonetheless, mitochondrial DNA modification is not without ethical complexity. Even if its direct functional role is narrower, it still involves heritable changes and the creation of embryos with genetic contributions from three individuals—the intended mother and father, and a mitochondrial donor. This raises questions about identity, kinship, and the rights of the resulting child, especially regarding disclosure and autonomy. Moreover, the long-term health effects of such interventions remain unknown. To prevent a gradual erosion of ethical boundaries, transparent ethical review processes and long-term clinical monitoring must be established as foundational requirements for any country considering the use of PNT.

From a clinical perspective, preimplantation genetic testing (PGT) should remain the first-line option for reducing the risk of mitochondrial disease transmission. PGT is a more established and less invasive method that allows for the selection of embryos with minimal or undetectable levels of pathogenic mitochondrial DNA. In many cases, this approach has proven effective and carries fewer biological and ethical uncertainties than PNT. In contrast, PNT is a more complex and experimental procedure that combines nuclear DNA from the parents with mitochondrial DNA from a donor egg, and it may result in lower fertilization rates or higher embryonic loss. Therefore, in keeping with the precautionary principle in bioethics, PNT should be considered only when PGT is not feasible or has been shown to be ineffective.

The United Kingdom currently leads in the clinical implementation of PNT, having established a strict licensing and regulatory regime through the Human Fertilisation and Embryology Authority (HFEA). The UK’s model reflects a commitment to enabling scientific advancement while maintaining ethical vigilance. However, reproductive technologies such as PNT are inherently transnational. If only a few countries offer access to such procedures, it may prompt “reproductive tourism”, whereby patients travel abroad to seek unregulated or less strictly governed treatments, potentially undermining safety standards and ethical norms.
For this reason, a coordinated international approach is urgently needed.

The World Health Organization (WHO) and the World Medical Association (WMA) are well-positioned to initiate global discussions and help formulate shared ethical guidelines and governance frameworks. These discussions should encompass not only scientific and medical dimensions but also social, cultural, and legal implications. Establishing minimum ethical standards and oversight mechanisms will help ensure that the benefits of PNT are pursued responsibly and that global health equity and ethical integrity are preserved.