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Posted on July 10, 2020 at 12:28 AM

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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