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Skepticism surfaces over CRISPR human embryo editing claims
When the first U.S. team to edit human embryos with CRISPR revealed their success earlier this month, the field reeled with the possibility that the gene-editing technique might soon produce children free of their parents' genetic defects. But the way CRISPR repaired the paternal mutation targeted in the embryos was also a surprise. Instead of replacing the gene defect with strands of DNA that the researchers inserted, the embryos appeared to use the mother's healthy gene as a template for repairing the cut made by CRISPR's enzyme.
But such a feat has not been observed in previous CRISPR experiments, and some scientists are now questioning whether the repairs really happened that way. In a paper published online this week on the preprint server bioRxiv, a group of six geneticists, developmental biologists, and stem cell researchers offers alternative explanations for the results. And uncertainty about exactly how the embryos' DNA changed after editing leaves many questions about the technique's safety, they argue. (The authors declined to discuss the paper while it's being reviewed for publication.)
Embryologist Shoukhrat Mitalipov of Oregon Health and Science University in Portland, who led the now-disputed experiments, released a statement saying that his team stands by its explanation. "We based our finding and conclusions on careful experimental design involving hundreds of human embryos," it says.
[...] Although the researchers inserted short strands of DNA as templates for repair, the cells didn't seem to take them up; those specific sequences were absent from the embryos. The cells must have relied instead on the nonmutated sequence in the egg donor's DNA when making the repairs, the team concluded.
The bioRxiv response, led by developmental biologist Maria Jasin of Memorial Sloan Kettering Cancer Center in New York City and Columbia University stem cell biologist Dieter Egli, challenges that interpretation. The authors, which also include well-known CRISPR researcher and Harvard University geneticist George Church, say that the Nature paper goes against conventional wisdom about how embryos are organized early in development. Right after an egg is fertilized, the DNA from the sperm and the egg aren't believed to be in close enough proximity to interact or share genes, they explain.
Previously: First Known Attempt at Genetically Modifying Human Embryos in the U.S. is an Apparent Success
U.S. Human Embryo Editing Study Published
Study in question: Correction of a pathogenic gene mutation in human embryos (open, DOI: 10.1038/nature23305) (DX)
(Score: 3, Interesting) by Immerman on Wednesday September 13 2017, @03:18PM (1 child)
Well, it could give you a clue, but just because it has no effect in mice doesn't mean it won't do something horrible to humans. And vice-versa of course. DNA expression can vary quite a bit between species.
There also seems to be something missing - my understanding is that CRISPR slices out a targetted segment of DNA, and then replaces it with it's payload. You don't just add some extra DNA strands as templates that get used by the cell for repair, CRISPR "welds in" your replacement.
If something else is going on, then that should be a huge red flag that either the researchers aren't actually doing what they're claiming, or that our understanding of CRISPR is woefully inadequate.
(Score: 0) by Anonymous Coward on Wednesday September 13 2017, @09:24PM
All CRISPR/cas-9 does is (preferentially) cut (introduce double strand breaks) at a certain target sequence. Once this happens, either
A) The cell dies
B) The break is fixed via NHEJ (non-homologous end joining), in which random errors will be found at the splice
C) The break is fixed via HDR (homology-directed repair), in which a DNA sequence with ends that overlap the cut ends is copied and inserted
It is important that A, B, and C are all done by enzymes/etc already present in the cell (the repair/death is "natural", only the cut is "artificial"). Before "gene editing" became a big deal it was commonly accepted that A >> B >> C for most systems, where ">>" indicates 10x - 1000x more likely. For studies like this, they largely ignore A and choose instead to come up with byzantine explanations for the strange results they get. In this case it appears the researchers were not familiar enough with developmental bio to anticipate critiques, so their explanation was deemed implausible.
The debunking here doesn't seem that convincing to me either though... instead it seems that the CRISPR/cas-9 material that gets in the cells can stay active through multiple cell divisions, so whatever is going on immediately after fertilization doesn't really matter.