How CRISPR lets you edit DNA – Andrea M. Henle


From the smallest single-celled organism to the largest creatures on earth, every living thing is defined
by its genes. The DNA contained in our genes acts like
an instruction manual for our cells. Four building blocks called bases are
strung together in precise sequences, which tell the cell how to behave and form the basis for our every trait. But with recent advancements
in gene editing tools, scientists can change an organism’s
fundamental features in record time. They can engineer drought-resistant crops and create apples that don’t brown. They might even prevent the spread
of infectious outbreaks and develop cures for genetic diseases. CRISPR is the fastest, easiest, and
cheapest of the gene editing tools responsible for this new wave of science. But where did this medical
marvel come from? How does it work? And what can it do? Surprisingly, CRISPR is actually a
natural process that’s long functioned as a
bacterial immune system. Originally found defending single-celled
bacteria and archaea against invading viruses, naturally occurring CRISPR uses
two main components. The first are short snippets of
repetitive DNA sequences called “clustered regularly interspaced
short palindromic repeats,” or simply, CRISPRs. The second are Cas, or “CRISPR-associated” proteins which chop up DNA like molecular scissors. When a virus invades a bacterium, Cas proteins cut out a segment
of the viral DNA to stitch into the bacterium’s
CRISPR region, capturing a chemical snapshot
of the infection. Those viral codes are then copied
into short pieces of RNA. This molecule plays many roles
in our cells, but in the case of CRISPR, RNA binds to a special protein
called Cas9. The resulting complexes act like scouts, latching onto free-floating
genetic material and searching for a match to the virus. If the virus invades again, the scout
complex recognizes it immediately, and Cas9 swiftly destroys the viral DNA. Lots of bacteria have this type
of defense mechanism. But in 2012, scientists figured out
how to hijack CRISPR to target not just viral DNA, but any DNA in almost any organism. With the right tools, this viral immune system becomes a
precise gene-editing tool, which can alter DNA and
change specific genes almost as easily as fixing a typo. Here’s how it works in the lab: scientists design a “guide” RNA
to match the gene they want to edit, and attach it to Cas9. Like the viral RNA in the
CRISPR immune system, the guide RNA directs Cas9
to the target gene, and the protein’s molecular scissors
snip the DNA. This is the key to CRISPR’s power: just by injecting Cas9 bound to a short
piece of custom guide RNA scientists can edit practically
any gene in the genome. Once the DNA is cut, the cell will try to repair it. Typically, proteins called nucleases trim the broken ends and
join them back together. But this type of repair process, called nonhomologous end joining, is prone to mistakes and can lead to extra or missing bases. The resulting gene is often unusable
and turned off. However, if scientists add a separate
sequence of template DNA to their CRISPR cocktail, cellular proteins can perform
a different DNA repair process, called homology directed repair. This template DNA is used as a blueprint
to guide the rebuilding process, repairing a defective gene or even inserting a completely new one. The ability to fix DNA errors means that CRISPR could potentially
create new treatments for diseases linked to specific genetic errors, like
cystic fibrosis or sickle cell anemia. And since it’s not limited to humans, the applications are almost endless. CRISPR could create plants
that yield larger fruit, mosquitoes that can’t transmit malaria, or even reprogram drug-resistant
cancer cells. It’s also a powerful tool
for studying the genome, allowing scientists to watch
what happens when genes are turned off or changed within an organism. CRISPR isn’t perfect yet. It doesn’t always make
just the intended changes, and since it’s difficult to predict the
long-term implications of a CRISPR edit, this technology raises
big ethical questions. It’s up to us to decide the
best course forward as CRISPR leaves single-celled
organisms behind and heads into labs, farms, hospitals, and organisms around the world.

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