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According to this Nature news article, a Chinese researcher claims to have made the world's first genome-edited baby using the popular CRISPR–Cas9 genome-editing tool. A gene called CCR5 was modified before the embryo was implanted into the mother. The CCR5 gene is known to produce a protein that is utilized by the HIV to enter human immune cells, and the genome editing performed is expected to make the babies HIV-resistant despite their father being HIV positive.

As a Chinese, I am deeply concerned with the ethical consequences and scientific impacts of this highly controversial experiment. However, to form an opinion for myself, I believe that I first need to know the potential dangers, either expected or speculated, that the twin babies might face in their life. Unfortunately I am not familiar enough with molecular biology to be able to know and judge these myself, and the reports in the media seem very vague on this issue.

So please let me ask: What are the potential dangers (if any) facing the twin girls, and how sure are we now about these dangers, their consequences, and possible countermeasures?

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    $\begingroup$ None of the research has been published, so nobody can say anything on this specific case, if it is even true. $\endgroup$ – canadianer Nov 27 '18 at 8:52
  • $\begingroup$ @canadianer, but the question is pretty general. There has been lot of debate about the dangers of genetically modifying embryos (off-target modifications/unexpected effects of targeted modifications). $\endgroup$ – Michael_A Nov 28 '18 at 7:01
  • $\begingroup$ @Michael_A Did I say otherwise? $\endgroup$ – canadianer Nov 28 '18 at 18:46
  • $\begingroup$ @canadianer I thought your comment could be read as pointing out a problem with the question. My comment was to highlight that there was no need to alter the question. Anyway, this is a secondary discussion. I'm out. $\endgroup$ – Michael_A Nov 28 '18 at 21:01
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Important notes:

I am not going into the ethical aspects of editing/removing CCR5 in human embryos, neither will I discuss potential effects of introducing that mutation into the human population. Both of these are very important issues, but out of the scope for this answer.
As of now I'm not aware of any reliable sources of what was actually done in this case, so I will also keep my answer general / hypothetical without going into any specifics of these particular girls.

That out of the way lets get into the potential problems that could be caused by removing the CCR5 gene from human embryo using the CRISPR-cas9 system. These can mainly be grouped into two classes: off-target or side effects of the procedure itself and any effects of a non-existing/functional CCR5 by itself.
One additional point I want to mention is that removal of CCR5 does not make one completely immune to HIV, because some strains of the virus (can) use the CXCR4 as a co-receptor instead.

1. CRISPR-Cas9 off-target effects

The CRISPR-Cas9 system has become very popular with scientists in the last few years, because it allows genome editing in very many organism with previously unmatched efficiency and speed. However, people only recently - when the potential medical use of the system was being considered - started to look into the specificity of the system. What they found was, that while CRISPR-Cas9 is supposed to be very sequence specific it often also induces mutations in genes that were not supposed to be targeted.
There is a quite a lot of ongoing research to reduce these off-target effects, one good example being to use two variant copies of the system that each only cut on strand of the DNA at neighbouring sites (instead of cutting both strands at one site as is normally done).
If such mutations occur while genome editing an embryo the possible effects are very hard to predict - it could be anything from completely harmless to cancer inducing. If one wants any reliable estimate for this, it would be necessary to check for any off-target mutations by sequencing the whole genome of the edited embryo. That however requires (even with very modern techniques) removing at least a single cell from the growing embryo before the IVF procedure can take place and might therefore reduce chances of the IVF being successful.

Main source: Extensive review to CRISPR off-target effects

2. Side-effects of CCR5 removal

Normally it would be very hard (read: basically impossible) to predict what potential side effects the removal of a specific gene would have, even if there are e.g. mice where this has already been done but only studied for specific medical aspects. In this particular case however, we are in luck because there is a naturally occurring mutation called CCR5-Δ32 that also renders the protein completely dysfunctional. We can therefore pretty safely assume that the CCR5 removal by CRISPR-Cas9 will have similar effects to this mutation.

Since CCR5 is a gene expressed by immune cells, it - unsurprisingly - has influences on various immune functions, but mostly seems to be affect infectious diseases. As this review puts it:

In summary, there are ample data to suggest that CCR5 is involved in both positive and negative regulation of immune functions that relate to the regulation of leukocyte trafficking during infectious and postinfectious diseases.

One particular risk that seems to correlate with non-functional CCR5 is both initial infection and disease progression by flaviviruses. It has been reported that the CCR5-Δ32 mutation increases the risk of being affected by both the Tickborne encephalitis (TBE) virus and West Nile Virus, both of which can affect the nervous system if the diseases progresses far.

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2019-09-29 update: the answer below is based on a scientific paper that seems to have a major flaw, see https://www.statnews.com/2019/09/27/major-error-undermines-study-suggesting-change-introduced-in-the-crispr-babies-experiment-shortens-lives/ (mirror): the 2 authors have requested that the journal that published their study, Nature Medicine, retract the paper.


The study {1} was published earlier this month and pointed out some side effects of the CCR5-∆ 32 mutation:

Abstract: We use the genotyping and death register information of 409,693 individuals of British ancestry to investigate fitness effects of the CCR5-∆ 32 mutation. We estimate a 21% increase in the all-cause mortality rate in individuals who are homozygous for the∆ 32 allele. A deleterious effect of the∆ 32/∆ 32 mutation is also independently supported by a significant deviation from the Hardy–Weinberg equilibrium (HWE) due to a deficiency of∆ 32/∆ 32 individuals at the time of recruitment.

The article {2} gives an interesting overview of the challenges to use CRISPR gene editing on embryos.


References:

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