* Nucleic acids are the 'NA'
in DNA, and are the building blocks of the DNA chain
The technique is being promoted as precise, and safer, than
old-fashioned GM. In fact, the debate
often stresses that nucleic acid editing is no different from random DNA
variation believed to happen all the time in Nature. One expert in the genetics of flowering
plants claims "This is a tool that creates what nature could create on its
own but just never got around (to) or had the opportunity to create". Such engineered changes in genes should,
therefore, "be seen as naturally occurring processes".
These views have been described by one review author, who
has worked with gene editing in the laboratory, as "too simplistic in
regard to both natural biological processes and the real potential of genome
editing". She points out, that
plants have evolved cellular mechanisms which "stop the progression of the
cell cycle where DNA damage is sensed, and also activate repair mechanisms to
protect distinct areas of the genome and to sustain genome
integrity". Put another way,
variations arising in DNA "cannot be considered to be purely random"
because they are the changes the cell didn't correct, and not because it
can't.
Gene editing mechanisms are very unnatural. They bypass natural limitations on what DNA
changes remain uncorrected, including vital sections of the genome highly
protected by the cell.
This latest gene-editing tool of choice borrows heavily from
bacterial CRISPR-Cas9 mechanisms for eliminating viral infections [1]. A specially-synthesized guide RNA* attaches
to a precise sequence of DNA linked to an adapted (or even entirely synthetic)
enzyme which converts the undesirable nucleic acid into the desired one. The guide tool has a second adapted enzyme
which cuts one side of the DNA ladder, activating the cell's own repair
mechanism which then changes the new nucleic acid's partner to fit it. Vectors used to ferry this guide-enzyme gene
editing complex into the cell include pathogenic bacteria and viruses. This process is unnatural from start to
finish.
* RNA is also a chain of
nucleic acids complementary to DNA
The assumption of 'precision' comes from software surveys of
the plant's DNA showing a lack of nucleic acid sequences elsewhere in the
genome which the guide RNA might latch onto by mistake. However, evidence from real-life gene edited
rice has shown that this type of survey is a poor predictor of actual guide RNA
target sites. In fact, some gene editors
induced "substantial genome-wide off-target mutations".
Part of the problem is that gene-editing 'precision' is
based on a concept of DNA as a neat, fixed, double, chain of paired nucleic
acids which the RNA-guide with its enzymes in tow can go to work on. Real-life DNA is highly dynamic, with chains
which move apart when actively generating proteins and may form all manner of
loops and bulges [2]. This provides a
huge scope for the RNA guide to grab hold of a passing section of
single-stranded DNA which in fact doesn't have to be a perfect match to the
guide.*
*Bearing in mind that
CRISPR-Cas9 evolved to deal with fast-changing viral infections, this fluidity
is hardly surprising.
Scientists in the field express confidence they can redesign
their gene editors to eliminate off-target editing, but in the context of
dynamic DNA, is it possible to do this without compromising the healthy
functioning of the DNA?
Nucleic acid editors have been thought to be safer than
older gene-editing techniques because they don't actually cut both strands of
DNA whose disconnected ends are prone to all sorts of mutations when they
re-connected. However, there's a
worrying trend of trivialising off-target edits as being 'relatively rare',
involving only one in the many millions of nucleic acids in the genome. A gene consists of a sequence of thousands of
nucleic acids, but changing a single nucleic acid can result in fundamental
alterations in the structure and function of the protein it codes for. (After all, that's why biotech scientists
want to edit the gene in this way in the first place!) Off-target nucleic acid changes could, all
too easily, generate novel toxins and allergens.
In plants, there are often many repeat copies of genes in
the genome, and plants with multiple sets of chromosomes ('polyploidy') are
common. Gene editors will alter all these
genes, with the possibility of a magnified outcome and magnified problems. This could never happen in nature.
Most science on gene editing is aimed at humans, promising deft repairs for genetic diseases. So, as the creators of nucleic acid editing say, "It is necessary to rigorously put the (gene) editors through their paces"" and "The community needs ... worst-case scenario pressure tests so we can make sure there's a good margin of safety when these agents do enter clinical trials".
OUR COMMENT
Off -target, and even on-target, gene-editing is clearly
unnatural and, equally clearly, has food safety implications.
We need that same 'good margin of safety' and clinical
trials before we eat gene-edited organisms too. Keep asking for it.
Background
[1] CRISPR/Cas9 GENE EDITING - March 2016
[2] KNOTTY DNA - July
2018
- Tina Hesman Saey, A CRISPR spin-off causes unintended typos in DNA, www.sciencenews.org, 5.03.19
- Karen Weintraub, CRISPR gene-editing will change the way Americans eat - here's what's coming, Guardian, 30.05.19
- Katharina Kawall, 2019, New Possibilities on the Horizon: Genome Editing Makes the Whole Genome Accessible for Changes, Frontiers in Plant Science 10
- New scientific publication shows differences between genome editing and conventional breeding, GM Watch, 4.05.19
- Jon Cohen, Novel CRISPR-derived 'base editors' surgically alter DNA or RNA, offering new ways to fix mutations, www.sciencemag.org, 25.10.17
- Shuai Jin, et al., 2019, Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice, www.sciencemag.org
- CRISPR spin-off causes unintended mutations in DNA, GM Watch, 13.03.19
- Jon Cohen, CRISPR offshoot still makes mistakes editing DNA, raising concerns about its medical use, www.sciencemag.org, 28.02.19
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