Representative edited human embryos (from Figure 4 of Hong Ma et al. Nature 2017, doi:10.1038/nature23305)
In a collaborative effort of US American, South Korean and Chinese laboratories, coordinated by the prestigious embryologist and primate specialist Shoukhrat Mitalipov from the Oregon Health & Science University, the authors publish a study where they have generated 142 human embryos (out of 167 oocytes set for fertilization) to investigate the possibility of correcting a mutation in the MYBPC3 gene associated with hypertrophic cardiomyopathy, through gene-editing, using CRISPR tools.
The findings reported in a Nature article published this week demonstrate the existence of previously unknown DNA repair mechanisms in human embryos that seems to be activated during a standard assisted reproduction technique: ICSI (intracytoplasmic sperm injection). Sperm cells co-injected with CRISPR reagents promoted the correction of the mutated gene through a homology-directed pathway that produces no genetic noise and does not generate mosaicism. Even more surprising is the fact that it appears to be unnecessary to provide a correct exogenous DNA sequence as a template to restore the mutated gene. The system was able to effectively use the unmutated copy of the gene in the oocyte as a template to direct the correction of the mutated gene brought by the male gamete. The reported correction efficiencies (greater than 72%), and the virtual absence of mosaicism and alterations in similar sequences (no detectable off-targets) confirm that we are dealing with an innovative method that may be utilized in future applications of genetic editing in human embryos.
These pioneer observations must be confirmed in other genes and diseases, before the described procedure could be considered a safe and effective practice. However, it escapes no one that successful genetic editing of human embryos is a qualitative leap, both technically and ethically, proving an innovative application of the use of CRISPR. This experiment, as described, could not have not been performed in many European countries as it would be illegal. For example, in Spain, it would conflict with the Oviedo Convention of 1997 (which USA did not sign) and the Biomedical Research Act of 2007, which prohibit the transmission of genetic modifications to offspring and the creation of human embryos to be used exclusively for experimentation, respectively.
At present, despite these encouraging findings, genetic editing in embryos should not be considered a procedure of choice. Actually, genetic editing in human embryos is something that today could only be considered for a small number of cases. For example, it would prove useful for couples in which one parent is homozygous for a dominant mutation that causes a serious disease, and whose children would necessarily inherit a copy of the mutated gene, thereby inheriting the disease. Or, it may be considered for use in couples where both have homozygous mutations in a gene associated with a congenital disease, whose children would necessarily inherit the mutation of the father and the mother and would develop the disease. For the vast majority of genetic diseases, we currently have robust and reliable techniques, such as preimplantation genetic diagnosis (PGD), which allows one to distinguish between healthy and mutant embryos and render it possible to select healthy ones for implantation.
The example used by the article, as proof of concept, is neither of the two previous situations. Being a heterozygote (a carrier of the dominant mutation), the male who participated in the study also had his other copy of the correct gene. Through a simple PGD this person, and his partner, after an in vitro fertilization, would have been able to select healthy embryos for implantation, without requiring any genetic editing.
About 50% of the resulting embryos would still carry the mutation and these would usually be discarded. This fact is well known to the authors of the study and they reason that their proposal could repair a significant percentage of these discarded embryos and thus increase the total number of embryos that could be implanted, provided that these embryos were authorized for implantation (which was not considered for the reported study).
While I appreciate the knowledge that this work brings about gene repair systems operating in human embryos – processes that we would continue to be unaware of in the absence of these experiments -, I still think that genetic editing in human embryos should not be, for the moment, a procedure of choice, mainly because there are other alternatives that are much safer and more effective, such as PGD, which would suffice for the vast majority of couples. The risks one would assume, apparently reduced after the innovative proposal of this article, and the potential benefits should be analyzed on a case-by-case basis, and the opportunity and the need would have to be ethically assessed before applying this still imprecise technique to alter the human genome.
I personally consider that, before dealing with embryo experiments, there are many more patients of congenital, incurable, rare (or not), existing diseases that could be subjected to somatic therapeutic approaches, treating the affected persons with virus-encapsulated CRISPR reagents or complexed with nanoparticles, to correct a significant, sufficient number of cells of the affected tissue or organ to allow for normal tissue function.
The preclinical experiments (in animal models, mice and rats) known so far for a dozen diseases, are very promising, and allow us to anticipate hope for the technique, when it would reach the required safety and efficacy for transfer to the clinic. I believe it is our responsibility, as scientists, to continue developing safe and effective treatments that may, in the near future, be used for the benefit of a large number of patients who now lack valid therapeutic solutions for their diseases or genetic conditions.
CSIC Research Scientist at the National Centre for Biotechnology (CNB) and CIBERER-ISCIII in Madrid, Spain; Member of the CSIC Ethics Committee; Former President of the ISTT (2006-2014)
Note: this article is an English translation of an opinion written by Lluis Montoliu and previously published at SINC, kindly edited by Jan Parker-Thornburg.