When asked why he wanted to climb Mount Everest, George Mallory famously quipped, “Because it’s there.” Today, a group of scientists, led by Shoukhrat Mitalipov at the Oregon Health & Science University, report in the journal Nature the successful use of a gene editing technology to correct a disease-causing mutation in viable human embryos. As biologists early in our career, we are skeptical that their motivation is any better than Mallory’s—and their endeavor comes with greater ethical concerns.
The focus of this study is a single mutation in the gene MYBPC3. This error is “dominant”—a child that inherits just one copy of the mutant gene is at high risk for a serious disease called hypertrophic cardiomyopathy, which can cause sudden cardiac death. Since each person has two gene copies and receives one randomly from each parent, a child with an affected father or mother has a 50 percent chance of inheriting the disease.
Using a gene editing technology called CRISPR/Cas9, Mitalipov and colleagues repaired the mutations in embryos created through in vitro fertilization (IVF) using sperm from a patient with the mutation and eggs from healthy donors. The key innovation of this study was simultaneously injecting the CRISPR machinery and a single sperm into an egg using an established IVF technique. Out of 58 embryos tested, 72 percent were mutation-free, compared with 50 percent of embryos in the control group. The edited embryos also appeared to develop normally until they were destroyed three days later. Importantly, the researchers did not detect any “mosaic” embryos, containing corrections in some but not all of their cells, or unintended mutations in other parts of the genome—challenges highlighted by a controversial 2015 study that attempted similar edits of nonviable embryos.
Since details of this study were leaked last week in the MIT Technology Review, there have been renewed calls to carefully consider the ethics of making heritable gene edits to embryos, eggs, and sperm. Concerns range from off-target effects and the inability of future generations to consent to genetic editing to the potential for Gattaca-style “designer babies.” In response, it has been correctly pointed out that the simplest clinical application is at least a decade off, and using CRISPR on embryos, eggs, and sperm, in contrast to other types of cells, is opposed by much of the scientific community.
There is an additional reason, seldom discussed, that this study and CRISPR research will not usher in a “brave new world” of eugenics: the genetics of most traits is too complex. For example, height is a simple trait that is easily measured and strongly determined by genetic factors. However, unlike in the case of hypertrophic cardiomyopathy, there is not a single gene determining height, but hundreds. A 2010 study found at least 180 genes that are associated with the differences in height between people, each contributing a small effect. Even if we could efficiently and safely edit individual genes using CRISPR, it will not be feasible to simultaneously edit hundreds of poorly understood genes in the foreseeable future. A recent study revealed that using CRISPR to edit just two genes can lead to disastrous chromosomal rearrangements. These fundamental stumbling blocks prohibit engineering more complex traits such as IQ, lifespan, and athletic ability.
Does this study at least mean that CRISPR may be used in the not-too-distant future to eliminate simple genetic disorders at the embryonic stage? Even this application has no clear utility, as inheritance of a mutant gene can be avoided with a simpler approach: pre-implantation genetic diagnosis (PGD). PGD is a procedure, in use since the 1980s, in which an in vitro fertilized embryo is tested for disease-causing mutations; mutation-free embryos are then selected for implantation. In the scenario explored here, in which one parent carries a dominant disease trait, 50 percent of embryos will lack the mutation; if both parents carried the mutation, 25 percent of embryos would still be healthy. Although discarding viable embryos carries its own ethical concerns for some, CRISPR will still require embryos to be tested and potentially discarded, even if the success rate is improved beyond the 72 percent reported in the Mitalipov study.
The use of CRISPR, as explored in this study, has no clear advantage over PGD. Mitalipov and colleagues claim that their approach could “increase the number of embryos available for transfer and ultimately improve pregnancy rates.” Even if CRISPR increases the percentage of mutation-free embryos during IVF, this marginal benefit is outweighed by the risks and ethical concerns it introduces. A recent National Academies of Sciences report on gene editing additionally considers a scenario where one parent carries two copies of a dominant genetic mutation, ensuring 100 percent inheritance of the mutation without gene editing. However, this motivation is also not compelling. Since the chance of having one mutant gene is rare, carrying two mutant copies, when not lethal, is vanishingly rare and typically limited to small, isolated communities.
If engineering human embryos with CRISPR has no clear application, why is it being pursued? At minimum, scientists conducting this research should confront its ethical dilemmas and offer sufficient justification for studies that may draw widespread opposition and fear. Such controversial uses of CRISPR may jeopardize the success of its less fraught applications. For example, CRISPR makes it easy to edit the genomes of many organisms that serve as new disease models. Additionally, ongoing work to apply CRISPR to adult cells may generate new treatments for diseases such as cancer and diabetes without the ethical concerns of embryo modification. We’ve only seen the beginning of the development of this transformative technology. While we can’t predict how CRISPR will develop, we can say that engineered babies are not around the corner.