As scientists repair a genetic mutation in a human embryo, the ethical debate has been revived.

Scientists have for the first time managed to edit genes in a human embryo to repair a genetic mutation, fuelling hopes that such procedures may one day be available outside laboratory conditions. In results announced in Nature a few days ago, scientists fixed a mutation that thickens the heart muscle, a condition called hypertrophic cardiomyopathy.

The cardiac disease causes sudden death in otherwise healthy young athletes and affects about one in 500 people overall. It is caused by a mutation in a particular gene and a child will suffer from the condition even if it inherits only one copy of the mutated gene. Correcting the mutation in the gene would not only ensure that the child is healthy but it would also prevent the mutation from being passed on to future generations.

In an attempt to remove the small portion of mutation, the researchers injected sperm of a man affected by hypertrophic cardiomyopathy and the gene-editing tool called CRISPR-Cas9, which cuts the DNA near the position of the mutation, into the egg at the same time. The gene-editing tool cut the DNA at the correct position in all embryos and 42 out of the 58 embryos did not carry the mutation.

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Thus the probability of inheriting the healthy gene increased from 50 to 72.4%. In the remaining 27.6% embryos, the DNA repair mechanism was not perfect as it had introduced unwanted additions and deletions of a few base pairs.

A DNA repair can take place by one of the two pathways. In the case of the non-homologous end joining (NHEJ) pathway, the breaks are repaired by randomly adding or deleting nucleotides, which leads to errors or changes in the DNA sequence. In the case of the homology-directed repair (HDR) pathway,  matching sequences are used to repair the DNA takes place. So in the case of 27.6% embryos where the repair mechanism was not perfect, the DNA  repair had taken place through NHEJ pathway.

A surprise

A surprising find was the cut portion of the DNA was repaired using healthy egg’s DNA as a template instead of the template with the correct base pairs that the researchers had introduced. Except the portion where the mutation was found, the DNA was found intact without any cuts and repairs in any other site of the genome.

Though the research marks a major milestone in genome editing of embryos, it will be a long while before it becomes available as a tool to produce healthy embryos. For instance, even research on embryos using federal funding is not permitted in the U.S., where the research was carried out. The embryos were produced with the clear intention of using them solely for research and not for implanting them in women.

While several diseases can potentially be prevented by using this technique, including some cancers, the announcement has also revived fears about designer babies being with the realm of possibility.

Can designer babies be made?

But as this article in the New York Times states, editing genes to repair single mutations — whether they cause disease or not — might be possible as was done in this case, but tinkering the genome even for diseases such as diabetes where several genes are involved and mutations might be more than one will be difficult. So producing babies for higher intelligence or other traits will remain in the realm of fantasy. According to the New York Times, tinkering the genome for simple traits such as height will be tough as height is estimated to be influenced by about 93,000 genetic variations, of which only 697 have been identified.

Also, as this work as demonstrated, even when the researchers had inserted a DNA template into the embryo, 42 of the 58 embryos copied the sequence from the healthy egg’s DNA and not from the template introduced. So, as per our current understanding, even if attempts are made to edit genes for certain traits by snipping out the sequence, there is greater likelihood that the required sequence would be copied from the egg’s DNA and not from the template that has been introduced.

Gene-editing tool will come to stay

In retrospect, every advancement in reproductive health, starting from in vitro fertilisation to the recent birth of a baby through the “three parent” technique for mitochondria-related disease, has initially been mired in controversy but has ultimately come to stay. In the same way, the use of CRISPR-Cas9 gene-editing tool when proven safe for preventing certain hereditary-disease causing mutations from being passed on to the child should be allowed, especially when no other treatment is available.

In February this year, the U.S. National Academies of Sciences and the National Academy of Medicine allowed scientists to use the tool for research and said the technique to edit embryos will become acceptable for clinical use. But for that to happen, rigorous research involving multiple locations has to be carried out to address all safety concerns and ethical issues.

To that end, the researchers have already addressed an inherent problem of producing embryos containing a mosaic of un-repaired and repaired cells by introducing the gene-editing tool and the sperm together into the egg. Mosaicism in later-stage embryos is produced when the gene-editing tool is used in a fertilised cell that divides to produce the cells of the embryo.  Meanwhile, the philosophical and ethical debates will rage on.

Published in The Hindu on August 5, 2017