Scientists have, for the first time, corrected a disease-causing mutation in early stage human embryos with gene editing. The technique, which uses the CRISPR-Cas9 system, corrected the mutation for a heart condition at the earliest stage of embryonic development so that the defect would not be passed on to future generations.

The work, which is described in Nature on August 2, 2017, is a collaboration between the Salk Institute, Oregon Health and Science University (OHSU) and Korea’s Institute for Basic Science and could pave the way for improved in vitro fertilization (IVF) outcomes as well as eventual cures for some of the thousands of diseases caused by mutations in single genes.

Though gene-editing tools have the power to potentially cure a number of diseases, scientists have proceeded cautiously, in part to avoid introducing unintended mutations into the germ line (cells that become eggs or sperm). The research in the current study adheres closely to guidelines established by OHSU’s Institutional Review Board and additional ad-hoc committees set up for scientific and ethical review.

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in otherwise healthy young athletes, and affects approximately 1 in 500 people overall. It is caused by a dominant mutation in the MYBPC3 gene, but often goes undetected until it is too late. Since people with a mutant copy of the MYBPC3 gene have a 50 percent chance of passing it on to their own children, having two genetic strands one faulty one not, being able to correct the mutation in embryos would prevent the disease not only in affected children, but also in their descendants.

The researchers generated induced pluripotent stem cells from a skin biopsy donated by a male with HCM and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair. The targeted mutated MYBPC3 gene was cut by the Cas9 enzyme, allowing the donor’s cells’ own DNA-repair mechanisms to fix the mutation during the next round of cell division by using either a synthetic DNA sequence or the non-mutated copy of MYBPC3 gene as a template.

Using IVF techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs newly fertilized with the donor’s sperm. They also tried a second method, introducing the gene editing components along with sperm into the egg prior to fertilisation.Then they analyzed all the cells in the early embryos at single-cell resolution to see how effectively the mutation was repaired.

The scientists were surprised by just how safe and efficient the method was using the second method ie. introducing the gene editor and the sperm prior to fertilisation and allowing the embryonic repair and replication process to identify the faulty gene as early as possible.

Not only did a high percentage of embryonic cells get repaired, but also gene correction didn’t induce any detectable off-target mutations and genome instability — major concerns for gene editing. In addition, the researchers developed a robust strategy to ensure the repair occurred consistently in all the cells of the embryo. (Spotty repairs can lead to some cells continuing to carry the mutation.)

“Even though the success rate in patient cells cultured in a dish was low, we saw that the gene correction seems to be very robust in embryos of which one copy of the MYBPC3 gene is mutated,” says Jun Wu, a Salk staff scientist and one of the paper’s first authors. This was in part because, after CRISPR-Cas9 mediated enzymatic cutting of the mutated gene copy, the embryo initiated its own repairs. Instead of using the provided synthetic DNA template, the team found, surprisingly, that the embryo preferentially used the available healthy copy of the gene to repair the mutated part. “Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos” says Wu.

Izpisua Belmonte and Wu emphasize that, although promising, these are very preliminary results and more research will need to be done to ensure no unintended effects occur.

“Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits,” adds Izpisua Belmonte.

Future work will continue to assess the safety and effectiveness of the procedure and efficacy of the technique with other mutations.

And reactions to the story in various newspaper seem to split into two basic camps: “this is brilliant, science at it’s best, leading us towards a glorious future that only primitives could disagree with” versus “this is satan’s work”.

It seems to me that the people so quick to condemn the doubters, are actually a bit naive about science and its often flawed nature. We are a long way away from any tangible good coming from this experiment and the ethical and moral questions it raises are considerable; something pointedly acknowledged by the scientists involved. An easier and quicker way to screen for this genetic disease would be to scan the sperm and filter out the faulty before using the healthy sperm to fertilise healthy eggs. Being able to cut and paste sperm in a petri dish, as opposed to sifting them to exclude the damaged,is an interesting intellectual exercise rather than a practical one.

The success rate when editing the faulty sperm prior to fertilisation was low. The scientists involved do not understand why or how the embryonic repair function works the way it does or indeed why it was so successful in choosing a healthy non-mutated copy of the gene as a template in replication.It may simply be that the genetic scissors attaches itself to the faulty gene and renders it somehow visible (and undesirable) to the embryonic replication system ie. the process was identifying and rejecting artificial intervention anywhere rather than anything more positive.

A surprising number of positive comments failed to distinguish between normal medical intervention, antibiotics, surgery, vaccination etc and genetic alteration that changes subsequent generations. A number seemed entirely content to compare gene editing with dog breeding, seemingly unaware of the obvious unintended yet damaging health implications in any number of dog breeds. The most fervent of supporters for the new research seemed surprisingly religious in their beliefs, with really a minimum of understanding and an awful lot of faith on display.

I have no patience with the idea that new scientific research is the work of the devil but I feel a bit uneasy about this messing about with our genetic heritage. We still know so very very little about how our genetic material interacts and operates that it seems inevitable that there will be some unintended consequences once we start messing about. I’m not so much fearful of deliberate malicious intervention, as I am of accidents where a scientist manages to fix problem (A) and three generations later we find that the IQ of a population drops 10 points, or that problem (A) also switched on some reaction in the immune system that would have allowed us to live an extra ten years without dementia.

It’s the unintended accident that worries me rather than the happy accident that this experiment seems to have discovered.