As humankind progresses into a new era of science and technology, many natural hazards have been eliminated and selection pressures lessened. While the natural evolution of the human species seemingly grinds to a halt, a new era of human enhancement takes the wheel — reproductive genetic technology.
by Michelle Tan Min Shuen
The human race is fickle, mutable, constantly evolving. Perhaps it is the reason behind our superior ability of self-preservation — 7 million years after our first human ancestors appeared on Earth, we have triumphantly emerged as the dominant species in the natural world.
Evolution has without a doubt led to an improvement in the wellbeing of the human species, but beneficial qualities take millions of years to become evident in the population. Not to mention, evolutionary changes were unable to satisfy our short-term desire for traits that are evolutionarily insignificant but that humans covet, like increased height, a specific eye or skin colour, or even intelligence level. As our understanding of the reproductive sciences improved with time, so did our cognizance that reproduction could be used as a tool to influence population demographics and shape one’s social milieu. Leaders with hidden political and social agendas began to strategise reproduction within a human population to promote the inheritance of “desirable” heritable characteristics such as race and intelligence, with infamous examples such as the Holocaust continuing to cast a long shadow over the field of reproductive biology today.
Such cruel and discriminatory practices have thankfully been phased out as humankind progressed into a new era of science and technology and adopted a new ethos. Yet our innate ambition for the improvement and betterment of the human race continues to push us towards a new age of human enhancement, one that fast-tracks the snails’ pace of natural evolution and eliminates the cruelty of historical eugenistic practises — reproductive genetic technologies (RGT).
RGT refers to technologies that either determine which potential future child to bring into existence based on predictions of their genetic composition, or alter the genetic composition of a given future child.
Familiar to most first-time parents of today’s generation would be prenatal testing — an RGT application that allows parents to learn more about their unborn child’s health through screening and diagnostic tests — which is extensively available in hospitals worldwide. Prenatal screening is non or less invasive and allows parents to know whether an unborn child has a predisposition to developing a certain condition. Pregnant women are typically recommended to undergo a procedure known as prenatal cell-free DNA (cfDNA) screening from week 10 of pregnancy onwards to screen for certain chromosomal abnormalities in a fetus. The procedure is non-invasive and only requires a sample of maternal blood to be drawn, from which DNA from the mother and fetus can be extracted and analysed to screen for foetal sex as well as to screen for certain chromosomal disorders, including Down syndrome (Trisomy 21), Trisomy 18, and Trisomy 13. For example, a higher than expected ratio of chromosome 21 sequences in the blood sample indicates an increased risk of trisomy 21 in the fetus.
On the other hand, prenatal diagnosis is typically more invasive and is performed after a fetus has been screened and identified to have an increased risk of a certain condition. The diagnostic tests performed definitively confirm whether the fetus has a specific condition. For example, invasive prenatal diagnosis by means of probes or needles being inserted into the uterus has long been used to prenatally diagnose chromosomal problems such as Down syndrome. Prenatal testing hence provides potential parents with insights on their unborn child’s genetic predispositions, allowing them to make a more informed decision on whether to go ahead with or terminate the pregnancy.
To some, there is nothing more exhilarating than watching parents ascend into euphoria after being showered with pink confetti upon bursting a gigantic black balloon. Avid users of social media application TikTok may be disappointed to hear that gender reveal parties, one of the hottest trends on the mobile app in the year 2020, may soon become a thing of the past as RGT allows parents to pick their unborn child’s gender becomes increasingly accurate and available to the masses.
Since the first in vitro fertilisation (IVF) was successfully performed in 1978, there has been a huge increase in couples using IVF to aid them to conceive. During IVF, mature eggs are first obtained from a woman’s ovaries and fertilised by sperm in a petri dish. Around three to five days later, one or more of those fertilised eggs are put into a woman’s uterus, where the embryo will continue to gestate for nine more months.
Historically, most of the clientele were couples who wished to conceive but experienced difficulties in getting or staying pregnant. With IVF, they were able to conceive a baby that was created ex utero. Today, recent innovations in the field have enabled couples to additionally determine the sex of the embryo created via IVF prior to being implanted in the uterus. This is done via a technique similar to the aforementioned technique of prenatal testing, known as preimplantation genetic diagnosis (PGD), used in conjunction with IVF. Using these techniques, many fertility clinics have been able to market “gender selection”. As IVF specialist Dr. Jeffrey Steinberg from one of such clinics noted, “The bulk of the patients that we see are doing in vitro fertilisation only to choose the gender [of the baby].” Notably, PGD is 100 per cent effective in attaining the desired sex, but it comes with a hefty price tag, costing up to US$20,000, almost double the cost of IVF treatment itself.
An alternative with a smaller price tag is an RGT that is still in a relatively infantile stage, having mostly been used for animal and livestock applications thus far. It is known as sperm sorting, which involves the separation of X-chromosome and Y-chromosome bearing sperm via flow cytometry to increase the probability of having a baby of the desired gender. Prior to flow cytometric sorting, semen is labelled with a fluorescent dye that binds to the DNA of each sperm cell. As “female” X-chromosome bearing sperm contain approximately 2.8 per cent more DNA than “male” Y-chromosome bearing sperm (due to the larger size of the X chromosome), it will absorb a greater amount of dye and fluoresce brighter than Y-sperm under UV light, allowing it to be separated based on this property during flow cytometry. The sorted sperm can then be used for IVF or artificial insemination. According to Steinberg, the accuracy for sperm sorting is about 78 to 80 per cent for females and 55 to 60 per cent for males.
The topic of germline genome editing was instantly bumped up to the global stage in 2018 when Chinese scientist He Jian Kui announced at the Second International Summit on Human Genome Editing that he had edited the genomes of two human IVF embryos using CRISPR-Cas9, a genetic engineering tool that uses nucleases and programmable guide RNA to modify specific genes. The father of the embryos was human immunodeficiency virus (HIV) positive, and the scientist attempted to create a specific mutation in the CCR5. gene (CCR5Δ32) that possibly confers the embryos with innate resistance to HIV. In actuality, his rushed 20-minute presentation spanning 60 slides was a futile attempt at concealing the fact that he had failed to perform germline editing safely, let alone effectively.
Theoretically, the idea was foolproof. By editing a gene in a single-cell fertilised human embryo, in principle, all cells produced as the embryo developed would then have the edited gene. However, while the scientist added the genes for CRISPR-Cas9 almost immediately after each embryo was created through IVF, some scientists predicted that CRISPR-Cas9 may have begun editing only after the embryo was past the one-cell stage, resulting in a mosaic which has a mixture of edited and unedited cells. True enough, He Jian Kui himself noted that the resulting twin girls, Lulu and Nana, still carried functional copies of CCR5 along with disabled CCR5.1 With a mix of corrected and uncorrected cells, the genetically modified twins are ultimately not resistant to HIV.
The inherent problem mosaicism present with the use of today’s germline editing technology is not one that can be easily ridden; there is presently no way to test cells in a developing multi-celled embryo for mosaicism, and matters with such lifelong implications are too important to be left up to a roll of the dice. Additionally, the CRISPR-Cas9 enzymes are error-prone and may potentially edit DNA at other sites with similar DNA sequences to the target site, resulting in off-target effects such as mutations in other critical genes, which may cause harm of unknown scales.
Three studies performed in 2020 also underscore the extensive on-target mutations that can occur at the target gene when the CRISPR-Cas9 enzymes repair the target gene. In one experiment, researchers used CRISPR-Cas9 to create mutations in the POU5F1 gene involved in embryonic development. More than one-fifth of the genome-edited embryos contained unwanted DNA rearrangements and deletions of several thousand nucleotides near the POU5F1 gene, highlighting how nascent and premature the technology is. “The on-target effects are more important and would be much more difficult to eliminate,” notes Gaétan Burgio, a geneticist at the Australian National University in Canberra. Not only is today’s technology not advanced enough to ensure that germline editing is efficacious, much more basic research targeted at the human genome and body is needed in order to prevent unnecessary off-target effects arising from gene editing.
Following the torrent of outrage and criticism directed towards the unethical creation of genetically edited twins, a group of leading researchers called for an international moratorium on germline editing involving eggs, sperms, and embryos, hoping to establish a process to discuss whether and under what circumstances, people should be allowed to make gene edits that have implications which are intergenerational in nature. The fact that germline modifications are heritable and can have an unpredictable effect on future generations further complicates matters as it skews the risk-benefit ratio of such research. Who are the research subjects, and what exactly are the risks involved? Until a consensus can be reached, regulated basic research on germline editing will remain at an impasse.
Even in a hypothetical scenario in which the targeting and precision of changes in genome editing were perfect, researchers express concerns that extensive meddling of the human genome could be a slippery slope towards their relative height would stay similar, and it is relative height rather than the absolute height that is associated with increased career and relationship success and subjective happiness.2 Rather, there may even be increased harm to society which has to accommodate taller individuals who consume more food resources and release more carbon emissions.2 Collective action problems aside, RGTs will only be able to be accessible to the upper echelons of society, exacerbating inequity and social unrest.
Such opinions may seem speculative for now, but with the rapid advancement of technologies and henceforth the capabilities of RGTs, it is only a matter of time before the lines between therapeutic and aesthetic applications of RGTs are blurred, and abstract concerns are shifted to reality. In fact, perhaps the story of Lulu and Nana will serve merely as a cautionary tale, reminding us that humanity will never truly be ready for the gargantuan impact of such revolutionary technology. “It’s difficult to say,” commented Abha Saxena, a bioethicist and former World Health Organisation advisor. “But humanity has always been adventurous.”
- Begley, S. (2018, November 28). Amid uproar, Chinese scientist defends creating gene-edited babies. STAT. Retrieved from https://www.statnews.com/2018/11/28/chinese-scientist-defends-creating-gene-edited-babies/.
- Gyngell, C., & Douglas, T. (2015, May 29). Stocking the genetic supermarket: Reproductive Genetic Technologies and collective action problems. Bioethics. Retrieved from https://pubmed.ncbi.nlm.nih.gov/24720568/.