CRISPR, the Technology That Revolutionized Gene Editing

We’re in Alicante, Spain, in the early 1990s. MTV, the Walkman, the best seasons of The Simpsons—everything we love to hate. Spanish researcher Francisco Juan Martínez Mojica is a bit adrift: he’s 30, short on resources, and facing a long road with no great triumphs—or great failures—ahead. Nothing out of the ordinary.

But he also has an interesting idea. Near his lab are the Santa Pola salt flats, a very, very salty place, obviously. The point is that there are organisms capable of surviving in those conditions: extremophiles—bacteria and archaea that live in salt flats, hot springs, and places where it’s hard to imagine life is even possible. So Martínez Mojica decides to sequence part of the genome of some bacteria from the salt flats. It’s the cheapest option, and maybe there’s something interesting in there.

A genome is a kind of recipe: it’s the information all individuals carry in a four-letter code (ACGT). Our genome, for example, is a sequence of something like 6 billion letters, including around 30,000 genes. Bacteria have much smaller genomes, but the relationship isn’t linear: corn, for instance, has a genome much larger than ours.

The history of DNA is spectacular. In 1870, scientists discovered there was “something” in the nucleus of cells. Only 80 years later, in the mid-20th century, it was confirmed that this something contained genetic information. In 1953, the structure of DNA was discovered and, around the same time, we understood how that information is read. A decade later, we started wanting to sequence the genomes of different species (especially the human genome), something that was only achieved in 2000, after almost 30 years of work and hundreds of millions of dollars invested.

But back to Martínez Mojica. When he obtained the sequences from those extremophilic bacteria—something that required quite a bit of work at the time—he found a series of very short repeated DNA sequences that caught his attention because they were regularly spaced. In other words, they repeated every certain number of letters along the genome of that organism. Soon, similar sequences started showing up in other bacteria. Francisco and his group figured that if these sequences appeared in so many organisms, they probably served an important function.

But the name was still missing. Until then, Martínez Mojica’s group—since almost no one else was working on the topic—called these sequences RSSR (short for Regularly Spaced Short Repetitions), a name that’s hard to say in any language. Try saying “RSSR” out loud and you’ll see. At a meeting with another group working on the same thing, they agreed to change it—and that’s how CRISPR was born, a much better name that works across languages: clustered regularly interspaced short palindromic repeats.

But the most important part of CRISPR is what Martínez Mojica’s group—and the groups that slowly joined in—discovered later. Little by little, the topic started drawing attention. These repeated sequences are expressed, meaning they’re transcribed into RNA, the way genes are. But instead of being translated into proteins, that RNA binds to proteins called Cas (short for CRISPR-associated proteins). There are several Cas proteins, but the most famous—wait for it—is Cas9.

Another key detail emerged when researchers studied CRISPR sequences and compared them with known genetic regions: they resembled parts of the genomes of certain viruses that infect bacteria. So even before anyone fully understood how, the hypothesis in the early 2000s was that CRISPR functioned as a bacterial defense system against viral infection. CRISPR kept gaining traction.

Things Start to Escalate

In 2008, something even more interesting happened: a group of researchers discovered that Cas9 attacks DNA by cutting it into small pieces, and that the RNA sequence (derived from those repeated segments) acts as a guide—like it’s telling Cas9 where to cut.

Shortly after, Jennifer Doudna’s lab determined the structure of Cas9 associated with CRISPR and saw that it functions like a molecular pair of scissors: it cuts DNA, guided by an RNA segment that points it to a specific target. Then someone had an obvious thought: if we change the guide, we can direct the scissors anywhere in the genome. Incredibly, it worked. Head-exploding meme.

In 2011, Emmanuelle Charpentier’s group in Switzerland uncovered the last missing piece: the CRISPR-Cas9 system works in vitro, outside bacteria. The next question was unavoidable: can we use this system to edit the genomes of other species?

In 2013, several papers were published at once describing CRISPR-Cas9 in different types of cells, including human cells. And so far, in every cell type where the technique has been tested, it has worked extremely well. Head-exploding meme times a thousand. We now have a remarkably simple system that lets us cut DNA wherever we want in the genome.

It’s not that genetic modification didn’t exist before CRISPR. In Argentina, for example, genetically modified cows existed years before CRISPR. The remarkable thing about CRISPR is how simple and cheap it is to use—and how it can target essentially any location in the genome, something that used to be far more limited. Because it requires relatively little equipment, the number of labs around the world with the capacity to genetically manipulate organisms multiplied exponentially.

Things Start to Get Messy

On November 25, 2018, He Jiankui uploaded a deeply disturbing video to YouTube. He’s smiling, wearing a light blue shirt, announcing that two babies had been born: Lulu and Nana. They were beautiful, he said, and they entered the world crying like any baby.

The catch is that Lulu and Nana had been genetically edited. Using CRISPR, the 34-year-old researcher cut the CCR5 gene, which HIV uses as a co-receptor to enter the cells it infects, in an attempt to make them immune to HIV.

The mutation he was aiming for exists in about 1% of the world’s population, who are, in fact, resistant to HIV. The problem is that this was done without any approved protocol for genetically editing human embryos that would later be implanted. And on top of that, he announced it on YouTube instead of publishing the work in a scientific journal, which would have been the normal path.

Worse still: the edit was performed at the one-cell embryo stage, meaning it would propagate throughout the entire organism—including the germline (the eggs, in this case)—so the change could be passed down to future generations. And to top off the disaster, the edit may not match the naturally occurring mutation precisely, so it’s unclear whether the twins are actually resistant to the virus at all.

His lab was shut down and he was sentenced to three years in prison. He was released not long after—and has since returned to work in genetics and artificial intelligence.

Plants

Plants are a separate story, and CRISPR disrupts everything there, too. Genetically modified crops have been grown worldwide for decades. In fact, the first genetically modified organism sold to the public was a tomato in 1994 (back when the Spaniard was still adrift). In Argentina, thanks to a decree signed by Felipe Solá, hundreds of thousands of hectares of GM crops have been planted since 1997.

So why did CRISPR spark such intense interest in plants if we’ve had transgenesis techniques for decades? The secret is Europe. GMOs are restricted in the European Union, and to trade produce with EU member countries it’s often necessary to demonstrate that no foreign gene has been inserted.

That’s where CRISPR-Cas9 has a major advantage. In principle, you can introduce Cas9 and the guide RNA to the site you want to modify, the system assembles, and the gene you want to change gets cut. But the CRISPR-Cas9 system itself doesn’t remain inserted in the genome. That means you can alter a plant’s genetic material without adding genes from another species. In other words, it isn’t a transgenic organism in the classic sense—so it can potentially navigate European restrictions more easily. That’s why there’s so much interest in CRISPR for plants.

Are We Ready for the Conversation?

In 1997, GATTACA premiered, starring Ethan Hawke, Uma Thurman, and Jude Law, all at a peak moment—Thurman was coming off Pulp Fiction, no less. The movie imagines a dystopian future where part of society (“the valid”) is genetically engineered to be long-lived, competent, and optimized, while the “invalid” arrive in the world the old-fashioned way.

What drives me crazy about the film is that in this dystopia, space travel is routine. The dream of the “invalid” protagonist is to pilot spaceships—a job reserved for the “valid.” Meanwhile, genetic manipulation is treated as normal. Today, almost 30 years after the film, regular space travel still feels far away, but genetic manipulation is right around the corner.

In the movie, there are also little machines that tell you whether you’re suitable or not—meaning they read your genome in seconds. That was unthinkable back then and is everyday life now. We could talk about the ethical dilemmas of 23andMe and how we hand over extremely valuable information, but we’ll save that for next time.

And it’s not all dystopias and embryo manipulation to make people smarter or, I don’t know, blond. There are hundreds of diseases that could potentially be treated with this technique. For instance, if someone has a genetic condition, cells could be extracted from that person, edited, and reintroduced “corrected,” in a way that wouldn’t be passed down to future generations. The person could be cured.

There are also close to 400 companies aggressively patenting all kinds of CRISPR-related technologies to implement someday. In other words: hundreds of companies building toward something that, in many ways, still isn’t fully here. But the eugenics implied by GATTACA—and much worse—is also a real possibility now, more than at any other point in human history.

So the question is whether we’ll be able to use this revolutionary technology for the good of humanity without screwing it up. I think we’ll screw it up a little and solve problems a little, as always. What’s certain is that this is already happening, and there’s no stopping it.

Doudna and Charpentier won the Nobel Prize in 2020. The poor Spaniard got nothing. In the early 1990s, he was a bit lost—and now we’re all a bit lost. In the end, it’s humanity.