The Controversial Pursuit of Gene-Edited Embryos
In 2018, when Chinese scientist He Jiankui announced the creation of the first genetically modified babies, the scientific community reacted with widespread condemnation, deeming the experiment reckless and premature. He subsequently faced imprisonment for his actions. However, the momentum surrounding genetically modified human embryos has not waned. Entrepreneur Cathy Tie argues that the advancement in this field is not only urgent but a “moral imperative.”
At just 30 years old, Tie has founded Origin Genomics, a company launched in March with the aim of integrating genetically modified embryos into in vitro fertilisation (IVF) clinics. In a recent publication in the journal Trends in Genetics, she advocates for public funding and new regulatory pathways to facilitate the clinical use of genetically modified babies. Nevertheless, significant concerns remain regarding the necessary testing to ascertain whether edited embryos are safe enough for human implantation, as well as the potential risks for newborns.
Hank Greely, a professor of law and director of the Centre for Law and the Biosciences at Stanford University, cautions, “There are cautionary tales from early human trials that showed no red flags, yet some individuals still perished.” This highlights the complexities and potential dangers associated with genetic editing.
Understanding Germline Gene Editing
The practice of germline gene editing involves altering the reproductive cells, such as embryos, with the potential for these changes to be passed down to future generations. For instance, this could provide a permanent correction for a devastating genetic mutation. However, unintended modifications in other regions of the DNA, known as “off-target effects,” could introduce new health risks that may also be inherited. This significant risk factor has led numerous countries to prohibit the genetic editing of embryos intended for pregnancy.
Couples at risk of passing on genetic disorders often turn to IVF combined with genetic screening to identify disease-free embryos prior to implantation. Critics of embryo editing contend that existing screening methods sufficiently reduce the need for such interventions. Greely suggests that embryo editing would only benefit a minuscule fraction of those in need.
The current IVF approach presents its own challenges, as it can be difficult to obtain viable embryos, even for individuals without hereditary disease risks. Ian Watts and Cheyenne Ziegler have undergone three IVF cycles in their quest to conceive children free from the genetic variant responsible for Watts’ Charcot-Marie-Tooth disease, a degenerative neurological condition affecting fine motor skills and movement. It is common for some oocytes not to fertilise in any given IVF cycle, and those that do often fail to develop properly or exhibit chromosomal abnormalities. Incorporating additional screenings for diseases means that some viable embryos may also not pass through the selection process.
The Hope for Genetic Editing
For Watts and Ziegler, their three IVF cycles resulted in eight chromosomally normal embryos, but only three lack the variant associated with Watts’ condition. This number is unlikely to be sufficient for the couple to achieve their goal of having three or four children. “At present, the options are either to remain childless or undergo multiple IVF cycles,” argues Watts, a 36-year-old engineer from Long Beach, California. Genetic editing could provide individuals like him with more opportunities to form families in the future. It may also assist couples in exceptionally rare situations where all embryos would inherit a disease-causing mutation, such as in cases where both partners carry two copies of a detrimental variant.
“We are here to treat these diseases, not merely to discard embryos and consider the matter closed,” asserts Tie, who is a former Thiel Fellow and has branded herself the “biotech Barbie.”
Precision in Gene Editing
In June, researchers from Columbia University revealed they had edited early-stage human embryos using a technique known as “base editing” with remarkable precision. Tie references this work in her article, arguing that precise editing is now within reach. If medicine can safely and effectively prevent disease, she contends that the decision to pursue such treatment should be part of patient reproductive choice. “The obligation of medicine is not only to avoid harm but also to prevent suffering when effective interventions are available,” she writes. However, she cautions that technology should not be employed to enhance traits such as intelligence.
Public sentiment appears to favour this option: a European survey published in July indicated more proponents than opponents of human embryo editing. Tie claims that Origin, based in New York City, is currently focused on “optimising” base editing and prime editing tools in human embryos donated for research by IVF patients. At this stage, the company is solely conducting tests on human embryonic stem cell lines. She anticipates that significant data demonstrating the safety and efficacy of their embryo editing tools will emerge in the coming months. Tie’s first venture into human embryo editing, Manhattan Genomics, abruptly shut down earlier this year after operating for just a few months.
Challenges Ahead for Gene Editing
While the Columbia study demonstrated that precise genetic changes in human embryos are feasible, the researchers did not correct disease-causing mutations. Some of the editing tools they developed also resulted in unwanted and inconsistent genomic changes, leading them to conclude in a recent Nature publication that the “undesirable consequences” indicate that the technology is not yet ready for clinical application. The variability in outcomes further complicates the landscape, as the success of one editing tool does not guarantee the safety of another.
Dieter Egli, who led the Columbia research, notes, “Thus, each mutation will, in itself, be a new drug.” In addition to the technical challenges, this could render the development of embryo editing particularly laborious and costly.
Financial and Regulatory Hurdles
Tie is clear in her belief that embryo editing is not yet ready for human patients but argues that it has advanced sufficiently to warrant addressing the legal and funding barriers that currently impede its development for clinical use in the United States. Federal funding for research involving human embryos is presently restricted by law, and the Food and Drug Administration (FDA) is prohibited from considering clinical trials involving genetically modified embryos.
Many scientists engaged in embryo editing are optimistic that it will eventually find its place in clinics. The debate lies in when this will occur and what criteria will determine its safety. Paula Amato, a professor of obstetrics and gynaecology at Oregon Health & Science University and advisor to the genetic editing company Preventive, posits that rigorous laboratory assessments of embryos will be necessary before proceeding to trials with non-human primates. These studies should also span multiple generations to ensure no unexpected changes occur. However, Origin is not currently working with animal models nor does it have immediate plans to do so.
Even with a seemingly effective editing tool in studies, it remains impossible to guarantee that any embryo implanted in a human will be free from unwanted genetic changes. Prior to transfer, edited embryos are likely to undergo genetic testing. However, embryo biopsies only extract a sample from a few cells, which may not accurately reflect whether different cells exhibit distinct genetic changes.
Assessing Risks and Future Possibilities
Undetected off-target effects could manifest years later, after a genetically edited baby has grown and had children of their own. “We will never be certain if we did our job correctly. One believes it is safe, but what is being transferred is a sort of black box,” describes Shoukhrat Mitalipov, director of the Centre for Cell Therapy and Embryonic Genetics at OHSU, who advised Manhattan Genomics. According to Amato, patients will need to be informed of these risks.
Watts and Ziegler assert that the potential benefits of this novel technology outweigh the risks, as it offers their affected embryos a chance at a disease-free life. Ziegler is currently 20 weeks pregnant with one of their unaffected embryos, but they have preserved those with Watts’ variant in hopes that one day it may be possible to correct them. “If the options are to discard them or give a chance to new technology, I would lean towards giving the new technology a shot,” she concludes.