A simple guide to CRISPR, one of the biggest science stories of the decade – Brad Plumer Dec 27, 2018, 2:45pm EST

It could revolutionize everything from medicine to agriculture. Better read up now.

One of the biggest and most important science stories of the past few years will probably also be one of the biggest science stories of the next few years. So this is as good a time as any to get acquainted with the powerful new gene editing technology known as CRISPR.

If you haven’t heard of CRISPR yet, the short explanation goes like this: In the past nine years, scientists have figured out how to exploit a quirk in the immune systems of bacteria to edit genes in other organisms — plants, mice, even humans. With CRISPR, they can now make these edits quickly and cheaply, in days rather than weeks or months. (The technology is often known as CRISPR/Cas9, but we’ll stick with CRISPR, pronounced “crisper.”)

We’re talking about a powerful new tool to control which genes get expressed in plants, animals, and even humans; the ability to delete undesirable traits and, potentially, add desirable traits with more precision than ever before.

So far scientists have used it to reduce the severity of genetic deafness in mice, suggesting it could one day be used to treat the same type of hearing loss in people. They’ve created mushrooms that don’t brown easily and edited bone marrow cells in mice to treat sickle-cell anemia. Down the road, CRISPR might help us develop drought-tolerant crops and create powerful new antibiotics. CRISPR could one day even allow us to wipe out entire populations of malaria-spreading mosquitoes or resurrect once-extinct species like the passenger pigeon.

A big concern is that while CRISPR is relatively simple and powerful, it isn’t perfect. Scientists have recently learned that the approach to gene editing can inadvertently wipe out and rearrange large swaths of DNA in ways that may imperil human health. That follows recent studies showing that CRISPR-edited cells can inadvertently trigger cancer. That’s why many scientists argue that experiments in humans are premature: The risks and uncertainties around CRISPR modification are extremely high.

On this front, 2018 brought some shocking news: In November, a scientist in China, He Jiankui, reported that he had created the world’s first human babieswith CRISPR-edited genes: a pair of twin girls resistant to HIV.

The announcement stunned scientists around the world. The director of the National Institutes of Health, Francis Collins, said the experiment was “profoundly disturbing and tramples on ethical norms.”

It also created more questions than it answered: Did Jiankui actually pull it off? Does he deserve praise or condemnation? Do we need to pump the brakes on CRISPR research?

While independent researchers have not yet confirmed that Jiankui was successful, there are other CRISPR applications that are close to fruition from new disease therapies to novel tactics for fighting malaria. So here’s a basic guide to what CRISPR is and what it can do.

What the heck is CRISPR, anyway?

If we want to understand CRISPR, we should go back to 1987, when Japanese scientists studying E. coli bacteria first came across some unusual repeating sequences in the organism’s DNA. “The biological significance of these sequences,” they wrote, “is unknown.” Over time, other researchers found similar clusters in the DNA of other bacteria (and archaea). They gave these sequences a name: Clustered Regularly Interspaced Short Palindromic Repeats — or CRISPR.

Yet the function of these CRISPR sequences was mostly a mystery until 2007, when food scientists studying the Streptococcus bacteria used to make yogurt showed that these odd clusters actually served a vital function: They’re part of the bacteria’s immune system.

See, bacteria are under constant assault from viruses, so they produce enzymes to fight off viral infections. Whenever a bacterium’s enzymes manage to kill off an invading virus, other little enzymes will come along, scoop up the remains of the virus’s genetic code and cut it into tiny bits. The enzymes then store those fragments in CRISPR spaces in the bacterium’s own genome.

Now comes the clever part: CRISPR spaces act as a rogue’s gallery for viruses, and bacteria use the genetic information stored in these spaces to fend off future attacks. When a new viral infection occurs, the bacteria produce special attack enzymes, known as Cas9, that carry around those stored bits of viral genetic code like a mug shot. When these Cas9 enzymes come across a virus, they see if the virus’s RNA matches what’s in the mug shot. If there’s a match, the Cas9 enzyme starts chopping up the virus’s DNA to neutralize the threat. It looks a little like this:

CRISPR/Cas9 gene editing complex from Streptococcus pyogenes. The Cas9 nuclease protein uses a guide RNA sequence to cut DNA at a complementary site. Cas9 protein red, DNA yellow, RNA blue.

So that’s what CRISPR/Cas9 does. For a while, these discoveries weren’t of much interest to anyone except microbiologists — until a series of further breakthroughs occurred.

How did CRISPR revolutionize gene editing?

In 2011, Jennifer Doudna of the University of California Berkeley and Emmanuelle Charpentier of Umeå University in Sweden were puzzling over how the CRISPR/Cas9 system actually worked. How did the Cas9 enzyme match the RNA in the mug shots with that in the viruses? How did the enzymes know when to start chopping?

The scientists soon discovered they could “fool” the Cas9 protein by feeding it artificial RNA — a fake mug shot. When they did that, the enzyme would search for anything with that same code, not just viruses, and start chopping. In a landmark 2012 paper, Doudna, Charpentier, and Martin Jinek showed they could use this CRISPR/Cas9 system to cut up any genome at any place they wanted.

While the technique had only been demonstrated on molecules in test tubes at that point, the implications were breathtaking.

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