Who would have thought our most advanced gene-editing tool would be carbon-copied from one of the most primitive life forms on Earth? But since 2012 the CRISPR molecule, which was first discovered in bacteria, has rapidly found its way into the pipettes of researchers everywhere.
It is faster, cheaper and more accurate than previous methods of tinkering with the genetic code. And with applications in treating human disease, agriculture – even designer babies – it’s no wonder the technology has created a storm of controversy. It has set us on the doorstep of a genetic revolution.
Here’s what you need to know.
What is CRISPR?
CRISPR is a molecule that finds a string of DNA code, locks on and makes a precision cut. And because scientists can tune it to target any genetic sequence, they can use it to turn genes off or replace them with new versions.
Short for “clustered regular interspaced short palindromic repeats”, CRISPR evolved in simple, single-celled microbes as a weapon for fighting off viruses. When viruses attack a bacterial cell, for instance, they inject a payload of their own DNA into the cell.
The cell responds by deploying CRISPR, which consists of a strand of ribonucleic acid, or RNA, hooked up to an enzyme called CRISPR associated protein, or Cas.
The RNA is primed to recognise and dock to the virus DNA, neatly encasing it in a pocket of the Cas enzyme. Cas, in turn, makes a cut in the DNA, which disables the virus’ attack.
Since 2012 scientists have tinkered with the CRISPR system in the lab to target not virus DNA, but genes in animal or plant cells. CRISPR alone can disable or “knock out” genes in cells. And if a strand of DNA coding for a new gene is added to the mix, CRISPR can be used to patch in a new gene between the chopped ends.
The recipe is fairly simple: a researcher designs and orders a piece of RNA that locks on to whatever gene they’re interested in, mixes it up with some Cas enzyme and voilà – they have cooked up their own customised precision gene-editing tool.
Because CRISPR has a strand of RNA that guides the target DNA into the enzyme, the system effectively sports a sensitive GPS, while other gene-editing methods work off a rough map.
RNA is a string of a four-letter code, which latches on to a target DNA sequence precisely, letter-by-letter. CRISPR’s two competitors, zinc-finger nucleases and TALENS, both rely on the shape of a protein to dock to the target. But they’re less accurate, which in the lab means more trial-and-error to edit a specific gene, making the process more costly and time-intensive.
CRISPR is also much faster at producing genetically modified mice – a standard workhorse for studying human disease in research labs.
Where traditional methods for creating mouse models involve breeding mice over a number of generations, CRISPR’s efficiency can create these mice in a single generation, slashing the time it takes to produce them by more than half.
What’s more, CRISPR can be used to tinker with multiple genes at once, useful for studying diseases which involve more than one gene.
Scientists hope CRISPR could one day be used to correct genes which lead to diseases in humans, or introduce genes which protect from disease.
But even though CRISPR is more accurate than other methods, it’s not perfect yet. The system can make “off-target” cuts in the genome, which means more tweaking is needed before we see it as a therapy in the clinic.
CRISPR’s track record
Beyond the medical field, CRISPR has big potential for agriculture.
Chinese scientists, for example, have used the method to produce a wheat strain resistant to powdery mildew, a fungal disease. Agricultural biotech giant DuPont is set to field-test CRISPR-edited drought-resistant corn and high-yield wheat, which the company says could hit the market in five years.
The US Department of Agriculture even recently gave permission for a common white mushroom – CRISPR-edited to prevent browning – to be cultivated and sold without GMO regulation. That’s because developers removed the gene for an enzyme from the mushroom rather than introduce new genetic material.
“I am confident we’ll see more gene-edited crops falling outside of regulatory authority,” Chinese Academy of Sciences plant biologist Caixia Gao told Nature.
Livestock may also see CRISPR on the horizon. Scientists at US start-up Recombinetics, for example, used CRISPR to engineer milk cows that don’t grow horns, aiming to save cows the painful ordeal of having horns removed with hot irons to prevent injury.
On the medical front, CRISPR has had success in treating human disease in animal models. In mice, scientists have used CRISPR to correct a mutation that causes muscular dystrophy and to disrupt a gene that causes Huntington’s disease.
CRISPR may also prove itself a new treatment for HIV. In March, a team of US scientists reportedly CRISPR-edited the HIV genome out of immune cells called T cells from an HIV patient. There’s still tweaking to be done, though – scientists recently reported CRISPR-editing can prompt the HIV virus to mutate.
But CRISPR has met controversy in its use in human embryos. That’s because changes made to genes of embryos are “germline” and can be passed on to future generations.
Two reports from research groups in China have outlined using CRISPR to edit human embryos – in one case to modify a gene responsible for a potentially fatal blood disorder, in the other to create embryos resistant to HIV infection.
In both cases, the embryos used were incapable of developing into a foetus, and success rates in both studies were low. CRISPR editing produced mutations away from the intended DNA target.
But experts gathering at the International Summit on Human Gene Editing, held in Washington last year, have not completely shut the door on germline CRISPR editing. They stated that it would be “irresponsible” to proceed with its clinical use until safety and efficacy issues were resolved and there was “broad societal consensus”.
Meanwhile, a team of British scientists was given the go-ahead to CRISPR-edit human embryos earlier this year. The researchers’ licence allows them to study genetically altered embryos for up to two weeks, to understand genes involved in early human development.
What’s next for CRISPR?
CRISPR is coming in on the medical front fast and furious, but rest assured – we won’t be seeing “designer babies” any time soon, if ever.
“Making a baby from gene-edited embryos … is a very bright ethical line that should not be crossed until the technology is proven safe and following an open discussion as to the benefit to society,” said cell biologist Amander Clark from the University of California, Los Angeles in response to the most recent report on human embryo editing.
For now, medical applications for CRISPR are confined to research labs. But as scientists iron out the kinks and the debate over the ethics of engineering human cells continues, we’re bound to see its application evolve.
Meanwhile, there is uncertainty over who has the right to commercialise CRISPR. The University of California, Berkeley and the Broad Institute of MIT and Harvard in Cambridge are locked in a battle over who first invented the technology.
What’s certain is that CRISPR is here to stay.
“I have seen gene editing technologies come and go – this one really seems like it has sticking power,” New York Law School patent lawyer Jacob Sherkow told Bloomberg.
“And that really ushers us into an age where the precise editing of DNA for whatever purposes human creativity can come up with seems possible,” he added.
Originally published by Cosmos as What is CRISPR?
Viviane Richter is a freelance science writer based in Melbourne.
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