CRISPR-Cas9 and the age of gene-edited humans

Genome or gene editing is when targeted changes
are made like insertions and deletions, right in an organism’s genome. Over the past decade, the CRISPR-Cas9 system
has become a very popular method of genome editing because it’s fast, cheap, precise,
and relatively easy to use. The way it works is that researchers create
a piece of RNA with a ‘guide’ sequence which is complementary to a targeted bit of
DNA in the host’s genome. In other words, if the DNA has a sequence
that reads 5′ -GGCTAT- 3′ , then the RNA guide sequence is exactly the opposite and
reads 3′ – CCGAUA -5′ And remember it’s a U for Uracil instead of a T for Thymidine
because the guide sequence is made of RNA and not DNA. The Cas9 protein then attaches to the RNA
and the whole thing binds to the target DNA sequence in the host genome. The Cas9-RNA complex then makes a double-strand
cut in the genomic DNA, and an alternative piece of DNA can be spliced in right at that
spot. CRISPR-Cas9 technology works in a variety
of cell types and organisms, and it’s been used to study diseases, and generate tissues
from stem cells, like heart muscle tissue and neuronal tissue. Now, it’s also possible to treat a whole,
multicellular organism with genome editing. For example, a mouse with liver disease due
to a genetic defect was treated with a CRISPR-Cas9-mediated genetic change, and it improved the mouse’s
symptoms. One important point to note about this mouse
example, however, is that the change was made to somatic cells, rather than germline cells,
meaning these genomic modifications aren’t passed to the next generation. That said, CRISPR-Cas9 technology is able
to alter the DNA in germline cells, and if that’s done, then the engineered changes
can be transmitted across generations. And this has been done in several organisms
including mice, monkeys, and most recently in humans. Last month, Chinese scientist He Jiankui,
claimed at a conference that he has edited the genes of twin girls using CRISPR-Cas9
technology. He specifically altered the CCR5 gene—making
the carrier resistant to some strains of HIV. He made the change In two embryos which were
then implanted in a woman and carried to term. Reportedly, the unidentified twins were born
and are healthy and at home with their parents. The announcement has lead to an international
moral outcry. First off, Jiankui acted in secrecy and did
not even tell his institution about his experiments. Second, it is not clear if there was proper
informed consent from parents before the procedure was done. Third the procedure didn’t have a known
medical need, since neither of the infants had an HIV infection, and the procedure inactivated
a healthy gene. Fourth, genome editing technology is still
in its infancy, and there’s no global consensus about using gene-editing technology on human
subjects. In addition, the risks of doing this to human
embryos remains difficult to predict. For example, according to Jiankui’s presentation
not every cell in the embryos was edited by CRISPR-Cas9. One possible outcome of this is that the twins
may be heterozygous for the edited gene, meaning each cell has a normal and edited copy of
the CCR5 genes, in which case they may not be resistant to HIV. Another is the twins may be mosaic, meaning
that some of their cells have two copies of the normal gene while other cells have two
copies of the edited gene, meaning that they’d only be resistant to HIV if the immune cells
end up having the edited gene. In addition, the mutation made to the CCR5
gene didn’t exactly match the known variation of the gene that confers HIV resistance. This means it’s not clear if these untested
changes will provide the same benefits, or introduce new unintended consequences. That said, while this research appears to
be rushed, and the fallout from it may have consequences that impact the scientific community
for years, there is support for the idea that germline genome editing of human embryos could
someday be used ethically to prevent devastating genetic diseases like cystic fibrosis or muscular
dystrophy. The general consensus is that we’re not
there yet, and that the scientists have moved quicker than the ethicists.


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