Genome Editing

[Angelica Cheng]

Permitting IVF polygenic testing is a slippery slope to genome editing in hyper-competitive Asian societies like Singapore

The Asia-Pacific region has seen rapid economic growth over the...

bioedge.org

 

[Angelica Cheng]

Should Singapore permit genome editing of human embryos? - UCA News

It’s unlikely given current government policy that biomedical regulation must conform to global consensus and standards

www.ucanews.com

Should Singapore permit genome editing of human embryos?​

A major biomedical breakthrough won the 2020 Nobel Prize for CRISPR technology for genome editing, which can potentially save the lives of many people afflicted with genetic diseases.

Currently, there is an international consensus that the use (or abuse) of genome editing for human enhancement is unethical. It is unethical to use genetic engineering to seek desirable traits in intellectual or athletic prowess, or physical characteristics such as skin color and height.

However, genome editing of somatic (non-reproductive) cells for curing genetic diseases is widely considered to be acceptable. And, currently, some clinical trials are going on in this area.

What has not yet been resolved are ethical issues in genome editing of human embryos and reproductive (germline) cells for preventing genetic diseases. This is best exemplified by the infamous case of the Chinese scientist He Jiankui, who was sentenced to prison for carrying out genome editing of human embryos to confer HIV resistance.

Such controversy would certainly be of interest to the ultra-rich and technologically-savvy city-state of Singapore, which has invested heavily in biomedical research in recent years, and developed a comprehensive system of biomedical regulations and ethical review.

There are some ethical and moral issues that Singapore has to resolve in deciding whether or not to permit genome editing of human embryos in IVF treatment.

No life-saving effort

As genome editing of human IVF embryos is not life-saving in itself but intended to save the life or health of a yet unborn future offspring, there is much less necessity and urgency as compared to curing patients who are suffering from life-threatening genetic diseases.

The key objective in this should be to enable patients with known genetic defects to have healthy genetically-related offspring of their own, rather than adopting a baby or resorting to egg donation.

This is in line with legal precedents in Singapore which stresses people’s desire to have children that carry their genes as a basic human impulse. It also aligns with the predominantly Confucian sociocultural values of Singapore that emphasize lineage continuity within traditional family formation.

Another major issue of contention is the availability of much safer and less complex options for preventing the transmission of known genetic defects to future offspring, in particular Preimplantation Genetic Testing (PGT) of human embryos. It raises a question: If PGT is a readily available option, why use genome editing?

The PGT is a mature technology platform with proven effectiveness in screening and weeding out various known genetic defects in IVF embryos. Compared to genome editing of human embryos, PGT is much safer as there are no permanent genetic modifications that can be transmitted to future generations. It is basically a technique for screening IVF embryos for inheritance of specific known genetic defects.

Nevertheless, there may be some cases whereby genome editing could be preferable to PGT. For example, the very few healthy IVF embryos typically produced by older women would only provide a small sample pool. This may not give much choice in the selection for non-inheritance of known genetic defects, so it may be worthwhile taking the risks with genome editing.

Moreover, older women tend to produce weaker lower-quality embryos that could make them more vulnerable to damage by cell extraction (biopsy) for genetic testing. Other cases may include rare instances whereby both parents are afflicted with the same genetic disease, particularly those involving dominant rather than recessive gene mutations, such as neurofibromatosis.

Yet another alternative would be to carry out gene therapy on the fetus while still in the womb. Upon prenatal diagnosis of genetic diseases, cells can be extracted from the fetus with advanced surgical techniques, subjected to genome editing, and re-transplanted back to the fetus. This is more easily achieved because millions of cells are available in the fetus, unlike the few cells of an embryo.

Redundancy of genome editing

Due to variable permutations in the recombination of different genes during the fertilization process, some embryos may inherit the known genetic defects of their parents, while other embryos may be healthy. Indiscriminate genome editing done on the entire batch of IVF embryos before ascertaining which of these carry known genetic defects by genetic testing (PGT) may unnecessarily expose healthy embryos to redundant genome editing, which could result in detrimental effects.

Here lies the contradiction. If initial genetic testing is required to screen genetic abnormalities in IVF embryos before genome editing; what then is the use of genome editing? Genome editing becomes redundant because some healthy embryos have already been identified during the screening process. Even in rare instances where all embryos are found to be genetically abnormal, the patient can simply attempt another round of IVF.

Cost-benefit rationalization

The occurrence of genetic diseases is relatively rare and even much rarer are instances whereby genome editing could be more advantageous than PGT in preventing transmission of genetic diseases.

The extremely small market size would question the commercial viability of genome editing of human embryos in IVF treatment, as well as its ability to boost Singapore's low fertility rate.

Safety issues in genome editing

Genome editing with CRISPR technology is neither completely error-free nor without potential risks. These include unintended on-target and off-target gene editing errors, and insufficient editing resulting in mosaicism, whereby only some but not all cells within the embryo have the correctly-edited genes.

The relatively small numbers of embryos typically produced by each couple during IVF treatment would thus impose severe limitations in screening out such gene-editing errors due to the extremely small sample size. By contrast, millions of non-reproductive (somatic) cells are readily available for genome editing and subsequent screening of gene-editing errors.

Furthermore, current knowledge of the complex interactions of genes involved in genetic diseases is still very limited, and there is always the risk that the detrimental side effects of genome editing may manifest much later in adult life.

More recently, a new study reported that CRISPR gene editing on human embryos may have dangerous consequences; because the cells of early human embryos often cannot repair DNA damage caused by the genome editing process, unlike other non-reproductive (somatic) cells of the human body.

Considering the various controversial issues and drawbacks associated with genome editing of human embryos for preventing genetic diseases, coupled with the extremely small market size and limited commercial viability, it may not be worthwhile for Singapore to invest and develop genome editing of human embryos in IVF treatment.

It is speculated that the only commercially viable and lucrative market for genome editing of human embryos could lie in its application for human enhancement rather than disease prevention. This is however unlikely to be permitted in Singapore, given current government policy that biomedical regulation in the country must conform to international consensus and standards.

 

[Angelica Cheng]

Ethics of germline genome editing to prevent genetic diseases from an Islamic perspective • PET

Dr Sayyed Mohamed Muhsin and Dr Alexis Heng Boon Chin give an ethical analysis of germline genome editing to prevent genetic diseases based on Islamic legal maxims (Qawaid Fiqhiyyah)...

www.progress.org.uk

Ethics of germline genome editing to prevent genetic diseases from an Islamic perspective

In 2018, Dr He Jiankui announced he created the world's first genome-edited babies (BioNews 977), which sparked a call for a five-year moratorium on germline genome editing. As this moratorium ends, it is timely to ask how do we progress from here?
As Muslims form a significant fraction of the world's population, understanding Islamic perspectives is crucial for the biomedical industry.
Currently, the overwhelming majority of Islamic scholars agree that genome editing for human enhancement, eg, to amplify traits such as high IQ, athletic prowess, height and complexion is prohibited (haram). This would be tantamount to tampering with God's creation (Taghyir Khalq Allah), as attested by several fatwas (Islamic religious rulings) issued by reputable Islamic organisations.
Nevertheless, germline genome editing to prevent genetic diseases still elicits some degree of controversy among Islamic scholars. Previous debates had mainly focused on safety aspects, informed consent and breaches of biomedical regulations. What have largely been overlooked are comparisons with alternative (possibly better) techniques for preventing or curing genetic diseases, and technical differences between germline versus somatic (non-reproductive) genome editing. Moreover, more recent research points to additional safety flaws of the CRISPR/Cas9 approach (see BioNews 1127). A fresh look is thus warranted.
To resolve conflicting opinions, it is best to critically examine whether this is aligned with Islamic principles based on Qawaid Fiqhiyyah (Islamic legal maxims) that incorporates Qaṣd (intention), Yaqin (certainty), Ḍarar (injury), Ḍarurah (necessity), and Urf (local customs).
This is often used as a roadmap in debates on Islamic bioethics, which usually requires an independent or original interpretation of new issues (Ijtihād) that are not explicitly mentioned by the Quran and Hadiths (prophetic traditions). Rather than providing a definitive answer as permissible (halal) or prohibited (haram), this approach facilitates a thorough examination of the issue at hand through the lens of well-established and universally accepted principles.
The first legal maxim related to Qaṣd (intention), refers to evaluating new medical technologies based on the intended objectives of its applications.
In this case, the key objective is to enable Muslims, who are carriers or affected with a genetic disease, to have healthy blood-related offspring of their own, rather than opting for Muslim-style adoption (Kafala). Resorting to gamete donation is explicitly prohibited by the Sunni branch of Islam, as this is considered akin to adultery (Zina).
This would thus align with one of the five key objectives of sharia law (Maqasid al-Shariah), namely the protection of lineage or progeny (Hifz al-Nasl).
The second legal maxim related to Yaqin (certainty) within the context of Islamic bioethics, refers to the current state of scientific knowledge and effectiveness of new medical techniques, and whether there are any safer or better alternative treatment options.
In this case, there is a much safer and less complex alternative technique – preimplantation genetic testing (PGT) of human embryos, a mature technology platform with proven effectiveness in screening various known genetic defects in IVF embryos, without any risks of permanent genetic modifications being transmitted to future generations.
Nevertheless, there may be some cases whereby genome editing could be preferable to PGT. For example, rare instances whereby both parents are affected with the same genetic disease, particularly those involving dominant rather than recessive gene mutations, such as neurofibromatosis.
It must be noted that due to variable permutations in the recombination of different genes during the fertilisation process, some embryos may inherit the known genetic defects of their parents, while other embryos may be healthy. Therefore, if PGT is required to screen genetic abnormalities in IVF embryos before genome editing; what then is the use of genome editing? It becomes redundant because some healthy embryos have already been identified during the screening process. Even in rare instances where all embryos are found to be genetically abnormal, the patient can simply attempt another round of IVF.
Yet another alternative would be to carry out gene therapy on the fetus in utero. Upon prenatal diagnosis of a genetic disease, cells can be extracted from the fetus with minimally-invasive surgical techniques, subjected to genome editing, and re-transplanted back to the fetus. This is technically easier to achieve because thousands of cells are readily-available from the fetus, unlike the very few cells of an embryo.
The third legal maxim related to Ḍarar (harm) questions the risks of potential harms associated with new medical techniques.
Genome editing using the CRISPR/Cas9 approach is neither completely error-free nor without risks. These include unintended on-target and off-target errors, and mosaicism, whereby only some but not all cells within the embryo have the correctly-edited genes.
The relatively small numbers of embryos typically produced by each couple during IVF treatment would thus impose severe limitations in screening out such gene-editing errors due to the extremely small sample size. By contrast, millions of non-reproductive (somatic) cells are readily available for genome editing and subsequent screening of gene-editing errors.
More recently, cells in early human embryos have been shown to be unable to repair the DNA breaks made during CRISPR/Cas9 genome editing process (see BioNews 1196).
The fourth legal maxim related to Ḍarurah (necessity), questions the necessity and/or urgency of using new medical techniques.
Because germline genome editing of human IVF embryos is not life-saving in itself but intended to save the life or health of a yet unborn future offspring, there is much less necessity and urgency as compared to curing patients who are affected by serious genetic diseases. Hence, it should be ranked lower in priority for public healthcare spending and Government-funded research, based on the Islamic concept of Fiqh al-Awlawiyyat (understanding of priorities).
The fifth legal maxim related to Urf (local customs), refers to taking into account local customs and traditions (if they are compatible with Shariah), when deciding on any new issues, such as novel medical techniques.
In this case, the devastating impact of serious genetic diseases on patients and their families is well-known. Hence there is almost universal public support worldwide for developing new medical techniques to prevent genetic diseases.
The pertinent question is whether germline genome editing is the best solution?

 

[Angelica Cheng]

Your Say: 3 reasons why S'pore is justified in restricting genetic screening of IVF embryos

I refer to the article “Baby Steps: 'Toughest period of my life', say women who underwent costly, emotional IVF process. Can more be done to support them?” (Feb 13).

www.todayonline.com

3 reasons why S'pore is justified in restricting genetic screening of IVF embryos​

I refer to the article "Baby Steps: 'Toughest period of my life', say women who underwent costly, emotional IVF process. Can more be done to support them?" (Feb 13).
It stated that some Singaporean couples travel overseas to do pre-implantation genetic screening (PGS) of their in-vitro fertilisation (IVF) embryos, due to restrictive regulations at home.
Currently, PGS is only open to women who are 35 and above, or those regardless of age who have two or more failed IVF procedures or two or more recurrent pregnancy losses.
In 2020, the Ministry of Health (MOH) said only 104 patients had undergone PGS thus far.
It is necessary to understand the various drawbacks of PGS and why it is so strictly regulated by MOH.
First, patients must be aware that genetic screening can potentially damage their embryo.
The technique is highly invasive, involving drilling a hole through the embryo shell and extracting cells for biopsy. This is potentially harmful and can impair its development.
Experts have pointed out that studies claiming no ill effects of PGS on embryos are often based on testing of excellent high-quality embryos rather than more "delicate" lower-quality embryos that might suffer more.
Because older women tend to have weaker lower-quality embryos, these may be more prone to damage upon testing.
Second, genetic testing is prone to misdiagnosis, which could result in patients discarding viable embryos that can give rise to a healthy baby.
This is because the testing involves extracting cells only from the outer embryo layer that produces the placenta and umbilical cord, which is not representative of the inner embryo layer that gives rise to the baby itself.
"Mosaic embryos" containing a mixture of genetically normal and abnormal cells have demonstrated the ability to self-correct and produce a healthy birth.
This "self-correction" mechanism involves pushing out the genetically abnormal cells into the outer embryo layer, which gives rise to the placenta and umbilical cord.
Older women have a limited number of embryos during IVF.
Therefore, excluding or discarding mosaic embryos that can potentially give rise to a normal baby, would substantially reduce their chances of IVF success. Some older IVF patients may have no embryos left to transfer after genetic testing.
Third, several large-scale clinical studies have shown that PGS does not improve IVF success rates.
In 2019, a large multi-centre randomised clinical trial involving 34 IVF clinics in the United States, Canada, United Kingdom, and Australia and including 661 patients aged between 24 and 40 years, found no significant overall improvement in IVF success rates with PGS.
In 2021, another large clinical trial in China, involving 14 IVF clinics and a total of 1,212 patients aged between 20 and 37 years, reported similar unfavourable results that were published in the prestigious New England Journal of Medicine.
Hence, based on the latest scientific and clinical data, serious doubts about the medical benefits of PGS have emerged, and current stringent regulation by MOH is thus justified.