CRISPR Babies May Eventually Become the Future of Human Reproduction, But Not in the Foreseeable Future

Elliot Stratton

ORCID: 0009-0001-1074-5837 

A Chinese doctor was imprisoned in 2019 a year after the birth of two genetically engineered CRISPR babies, sparking heated controversy and debate worldwide (Wee, 2019). Here’s where the “designer babies” debate stands four years later, and why CRISPR’s powerful gene editing capability must be implemented with extreme caution to improve fertility practices and genetic disease outcomes in future generations. 

A Reputation Shattered 

In 2019, after widespread condemnation from the public and scientific community for his gene-editing experiments, biophysicist Dr. He Jiankui was sentenced to three years in a Chinese prison for “illegal medical practices” (Wee, 2019). Dr. Jiankui edited human embryos, which, in November 2018, became the world’s first genetically engineered babies – twin girls given the pseudonyms Lulu and Nana (Wee, 2019). While astonishingly little about the experiment is publicly known, and most of the disclosed information has come from Dr. Jiankui himself, the experiment aimed to use a recently discovered gene editing technology called CRISPR to prevent the development of AIDS in humans. This was to be accomplished by a deletion of 32 nucleotide base pairs in a gene called CCR5, which is responsible for the production of a white blood cell protein targeted by HIV during bodily invasion (Greely, 2019). 

In both children, it appeared that the protein produced by the edited CCR5 gene was nonfunctional, though the specific 32-base pair deletion had not been executed according to plan (Greely, 2019). Even with gene targeting and specificity being a promising attribute of CRISPR technology, some cells in the twins from Dr. Jiankui’s experiment exhibited CCR5 genetic modifications while others did not, demonstrating mosaicism in both twins. Such a condition occurs when a person has more than one set of genetically different body cells, and while the long-term effects are not fully known, they are rarely predictable (Ma et al., 2017). This development in both twins raises questions about the potential unintended consequences of human embryonic genetic editing, which may not emerge until after birth. Perhaps even more reprehensibly, Dr. Jiankui’s alteration of CCR5 within human embryos was a form of germline genetic editing, whereby the descendants of his experiment may pass on the same edited gene (of which long-term consequences are unknown) to their offspring if they choose to have children (Alonso & Savulescu, 2021). Additionally, the court responsible for Dr. Jiankui’s prison sentencing found evidence of forged documents falsely claiming approval from ethical review boards for his study (Wee, 2019). Dr. Jiankui crossed several established bioethical standards when he proceeded with the birth of genetically engineered babies, and while his research has since become exemplified for what not to do in the field of genetic engineering, it has sparked conversation worldwide about how best to proceed with so-called “designer babies.” Was it possible that Dr. Jiankui was on to something? Can we use Dr. Jiankui’s experiment to not only improve future adherence to principles of bioethics but further examine the impact of gene editing and in-vitro fertilization to eliminate crippling genetic conditions or reduce disease susceptibility before birth? The answer may be a complicated, convoluted, and controversial yes.

Choices, Choices, Choices

To better understand the ethical concerns of Dr. Jiankui’s experiment and CRISPR as a gene editing tool, it is crucial to first discuss the established technologies influencing the favorability of fertility outcomes. Preimplantation genetic diagnosis (PGD) is the current and most commonly used procedure for influencing the genetic makeup of a newborn, a process beginning with in-vitro fertilization (IVF). Occurring outside the human body after the collection of both eggs and sperm, IVF of an embryo is performed using one of two methodologies. In most situations, egg and sperm are permitted to interact naturally in a culture dish to create a fertilized embryo. However, in cases where offspring inheritance of a single-gene disorder is a concern, a procedure called Intracytoplasmic Sperm Injection (ICSI) may be used instead. This process involves the laboratory-assisted penetration of sperm into an egg, from which a fertilized embryo is created (Pre-Implantation Genetic Testing, n.d.). In either case, the cells of the embryo are given time to grow and multiply outside the uterus before undergoing testing for genetic abnormalities. Because the results of genetic testing are known prior to uterine implantation, parents can select an embryo for a child that will have a reduced or non-existent risk of a specific genetic disorder or disorders (Sciorio et al., 2021). PGD has shown considerable effectiveness as a tool for desirable pregnancy outcomes that, unlike CRISPR, does not involve any cutting or manipulation of embryonic DNA.

Since its inception in the 1990s, PGD has become established as a preferred method for minimizing offspring susceptibility to over 600 different single-gene and sex-linked disorders (Sciorio et al., 2021). Popular as an alternative to amniocentesis or chorionic villus sampling – measures of prenatal diagnosis only available at later stages of pregnancy –PGD allows couples to choose an embryo minimizing the risk of inherited genetic disease prior to fetal development (De Krom et al., 2015). The ethical underpinnings of PGD are reinforced by global clinical research studies, which have supported PGD as a safe fertility practice. Compared with rates of congenital malformation in naturally conceived births, nearly 20 years of Dutch natality data indicates that babies born from PGD and IVF/ISCI embryos are not at a higher risk of birth defects (Heijligers et al., 2018). In another study of women at advanced maternal age (ages 38-41), it was found that PGD screening specifically for aneuploidy –a condition characterized by abnormal embryonic chromosome counts – improved pregnancy outcomes and reduced miscarriage risks compared to those who had not undergone such screening (Rubio et al., 2017). As evidenced by these studies, PGD performed responsibly and ethically represents an alternate path to fertility for couples concerned about the genetic health of their offspring.

Where PGD Falls Short, And Where CRISPR Could Contribute to Both the Problem and Solution

As versatile as PGD can be in detecting single-gene disorders, sex-linked diseases, and chromosomal abnormalities, there are several scenarios in which PGD cannot accurately predict or influence genetic disease inheritance (Sciorio et al., 2021). If both parents are homozygous even for a single gene contributing either to an autosomal dominant disorder or an autosomal recessive disorder, PGD cannot prevent the offspring from inheriting the gene leading to the condition. For the many polygenic disorders, disorders that are influenced by genes on several different chromosomes, finding a suitable implantation embryo without disease-associated genes is often impossible (Ranisch, 2020). These shortcomings of PGD have directed the spotlight on CRISPR as a tool with the potential to not only treat genetic diseases after birth but potentially prevent them from occurring through embryonic gene editing prior to uterine implantation. However, as exciting as this prospect may seem, we as humans are still far removed from this reality.

CRISPR, in a reproductive context, is a fundamentally different technology from PGD –one that focuses on the editing of specific embryonic genes as opposed to the selection of an entire embryo containing (or lacking) a certain gene of interest. As such, CRISPR’s versatility to alter specific genes of interest has generated a flurry of scientific conversation – and plenty of controversy (Ranisch, 2020). The idea of CRISPR being used to safely correct mutated alleles before uterine implantation (without adverse consequences) would appear to be a logically sound argument for embryonic DNA manipulation. From a limited number of laboratory trials, however, CRISPR as a tool for germline editing has not produced such ideal results. CRISPR has demonstrated an ability to recognize specifically targeted sequences of DNA, though it also has initiated unintended alterations to DNA located outside an intended area (Zuccaro et al., 2020). Highly consequential off-target effects of CRISPR were observed in a study of human embryos edited to repair a gene influencing hereditary blindness. Despite the intent of researchers to make one cut in the gene of interest on chromosome 6, about half of the edited embryos showed detrimental and/or non-survivable DNA loss on the same chromosome (Zuccaro et al., 2020). Researchers targeted MYBPC3 in another study of human embryos, a gene associated with an increased risk of hypertrophic cardiomyopathy. This condition, which is influenced by genetics and characterized by heart muscle enlargement, is known to reduce cardiovascular efficiency and increase the risk of serious cardiac events (Ma et al., 2017). Through direct injection of Cas-9 protein into the embryos, the risk of mosaicism was greatly reduced after alteration of the MYBPC3 gene, but still not eliminated. Interestingly, this study found no evidence of off-target mutations resulting from CRISPR modification, though it is unclear whether the technology used to detect mutations was sufficiently accurate (Ma et al., 2017). While the lack of off-target effects in this study is promising, the risk of mosaicism and its associated uncertainties remain too high to justify the embryonic use of CRISPR. Dr. Jiankui’s infamous experiment serves as further evidence of both off-target and mosaic consequences of germline genetic editing, for which the long-term consequences are still unknown. Though Lulu and Nana appeared healthy at birth, little is known about their current health or the possibility of negative CRISPR-related outcomes occurring in later stages of their lives. Collectively, these studies demonstrate that embryonic gene editing with CRISPR is far from polished and is accompanied by many poorly understood risks and outcomes. Until the scientific community can identify and mitigate these adverse consequences through sufficient testing and research, CRISPR cannot be ethically implemented on human embryos –at least not in the foreseeable future.

While CRISPR may be in its rudimentary stages as an embryonic germline gene-editing tool, this recently developed technology has demonstrated more promising results in the realm of post-birth somatic genome editing. Compared with the alteration of the germline genome, which impacts the genetic inheritance of an embryo and its future generations of offspring, the genetic outcomes of somatic genome editing in body cells are non-inheritable and cannot be passed down (Zuccaro et al., 2020). As such, CRISPR has become a focus of numerous clinical trials with the intent to improve outcomes and reduce unpleasant symptoms of genetic diseases and cancers after birth. Victoria Gray, the first of several patients with sickle cell disease to receive a transplantation of CRISPR-modified bone marrow cells, has optimistically reported living symptom-free four years after her procedure alongside 31 other patients successfully receiving the same treatment (Stein, 2023). Several recent studies have also pointed to CRISPR-modified chimeric antigen receptor T-cell (CAR-T) immunotherapy as a new and promising technique to target specific genes associated with certain cancers (Naeem et al., 2023). Even as CRISPR may not be an ethical approach to germline genetic editing, at least in the foreseeable future, its application in somatic gene editing and disease treatment remains less controversial and accumulates scientific support. 

How do We Move Forward?

It is difficult to justify the current use of CRISPR for germline editing, even in cases where PGD is futile for preventing inherited conditions in offspring. Even with a limited degree of progress observed in some studies, the risk of unintended off-target consequences in embryonic DNA edited with CRISPR is still far too high to allow ethical use. Given their ease of heritability, the outcomes of mistakes in germline genome editing could potentially be irreversible if done improperly (Ranisch, 2020). Until the ability to detect mosaicism and off-target mutations greatly improves, and the accuracy of CRISPR does too, no genetically engineered embryo can responsibly and ethically be carried to term. The He Jiankui experiment has demonstrated firsthand the risks of CRISPR as a tool for germline editing, the outcomes of which should not be replicated until sufficient scientific evidence is available to support the safe delivery of a genetically engineered child. As unlikely as concrete results may be in the immediate future, the research is nevertheless worthwhile for its potential to improve outcomes of human conception. 

While progress is made toward a better understanding of germline genetic editing, PGD remains the most viable option for minimizing or preventing offspring from inheriting a genetic disorder prior to birth. Though not always applicable for all parents looking to conceive, continual improvements to genetic screening methodologies have boosted the accuracy and scope of PGD, especially for the detection of neurological disorders (Sciorio et al., 2021). The selection of an appropriate embryo, as opposed to DNA manipulation, represents a much safer methodology for minimizing offspring risks of genetic disease without the risk of CRISPR’s documented off-target consequences. The terms “promise” and “potential” are often used when discussing CRISPR, and although the technology has the capacity to improve human reproductive health, society is just not there yet. Moving forward, the focus of CRISPR research ought to fill in gaps currently left open by PGD while focusing almost exclusively on genes influencing physiological health. Though currently in its elementary stages, pending substantial, comprehensive, and cautious scientific research, CRISPR’s usage as a tool to improve post-birth outcomes of offspring is poised to usher in a new chapter of reproductive health.

References

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