A new cautionary tale for heritable genome editing

A fundamental concern about applying gene editing to human embryos is how to limit the risk of errors, or “off-target” effects.  One makes an edit to change a bad gene’s defect, and presumably prevent the disease the defective gene would cause.  But the current methods to do that, although apparently highly selective, might still make other, unwanted changes as well—with possible deleterious, even disastrous, consequences.

Heretofore, the attention to these “off-target” effects has largely been directed to changes in genes that are separated from the target gene.  However, a recent news item in Nature describes three recent experiments with human embryos in the laboratory, in which large defects were induced in the chromosomes bearing the target gene—that is, right next door.  The difference is a bit like the difference between damage by shrapnel (distant effect) and blowing a 6-foot hole instead of a pinhole (near effect).  The latter is now the new concern.  Apparently, and, for one who does not live the scientific details daily, amazingly, prior analytic techniques were missing the possibility of these big, close-in errors.  “CRISPR gene editing in human embryos wreaks chromosomal mayhem,” the headline reads.  Geez Louise…

The technical details are still to be worked out, but one possibility is that, after the targeted gene is cut by the editing mechanism, the way that repair of the genes is done by the human embryo creates the possibility of introducing errors by copying or shuffling of a big chunk of the gene.  These processes are not fully understood in human embryos, and may be different from what pertains in mouse or other animal embryos, or in single human cells such as egg cells or newly-fertilized eggs.

The big technical message is that a lot is poorly understood and will take a ton of work to sort out before one can be confident that a pregnancy carrying a gene-edited to-be-born human will birth a healthy baby, in the immediate outcome, never mind consequences later in life.  It further suggests that no amount of animal work may lay the matter to rest.  From that it’s hard to avoid the conclusion that many embryos will need to be created, altered, and destroyed for research purposes if heritable human genome editing is to proceed with some assurance of safety.  How long would those embryos have to be kept alive to test?  Quite possibly longer than the few days currently possible and accepted by the scientific community.

Absent that, trying to birth gene-edited children would mean, as this blog said some time ago, that “the babies are the experiment.” 

And, even if one does not grant moral status to the human embryo from the point of conception, one is compelled to seek an accounting of the compelling unmet medical need that supports a careful benefit-risk analysis.  Risks to human subjects—embryos, fetuses, eventually-born babies, women donating eggs, perhaps even women carrying partial pregnancies (to allow study of results from a later point in utero?)—seem substantial, overall costs of the effort raise questions of spending the money better elsewhere in the overall health care of society, and alternative approaches to the diseases in question must all be considered.

Geez Louise.

One other point: the Nature article cites preprints posted, prior to peer review of the science, on the website bioRxiv.  Operated by the outstanding Cold Spring Harbor Laboratory, the website offers authors the chance “to make their findings immediately available to the scientific community and receive feedback on draft manuscripts before they are submitted to journals.”  Open access and public feed back are good, but the general press often picks up these preprints, whose quality may not have been fully vetted, and runs with headlines—kind of like I am doing here, following Nature.  So we must watch this space to be sure that the research is being accurately described and interpreted.  For the moment, the topic of this post can be taken as another example of “something to watch out for.”

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