Jennifer Doudna:Emmanuelle Charpentier_10th Anniversary
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As Crispr Turns 10, Its Medical Promise Comes Into Focus

The gene-editing tool has transformed the study of human disease, but before it can revolutionize treatments, researchers will need to solve three basic problems.

Ten years ago this week, a report of new research quietly appeared on an academic journal’s website — and caused a seismic shift in science. Biochemists Jennifer Doudna and Emmanuelle Charpentier adapted a tool called Crispr-Cas9 to snip genes from bacteria. When Feng Zhang, another biochemist, and others later showed that the same tool could be used to edit human cells, the magnitude of Crisper’s potential became clear: It could one day be used to create treatments — perhaps even cures — for a range of genetic diseases.

In the decade since, tens of thousands more papers on Crispr have been published. Its inventors have collected virtually every scientific award, including the Nobel Prize. Dozens of public and private Crisper biotech companies have been formed.

And Crispr-based therapies are being tested in humans — including one that is close to market. Later this year, Vertex Pharmaceuticals and Crispr Therapeutics are expected to seek approval for a one-time treatment for two rare blood disorders: sickle cell disease and beta thalassemia.

Did Doudna, in 2012, see how fast all this would happen? “In a word: no,” she told me in a recent conversation about the future of Crispr. Nor is the path forward assured. Crispr will not fulfill its medical promise until researchers solve three significant problems.

The Delivery Challenge

Crispr is astonishingly good at editing DNA — in the lab, that is. The challenge is getting Crispr inside the right human cells to do its job. Turning Crispr into a drug that can edit cells inside the body (“in vivo” editing) stands to dominate research efforts over the coming decade.

Right now, two strategies are used to sneak Crispr into the body: hollowed-out viruses, known as viral vectors, and lipid nanoparticles, the same fat bubbles that are used to deliver mRNA Covid vaccines. Most Crispr companies seem to prefer the fat bubbles, but the trouble with these is that they head straight to the liver. That makes it relatively easy to address any disease involving the liver. Early data from Intellia show that, unlike many other new technologies, Crispr works amazingly well in the liver. But it’s hard to use lipid nanoparticles to target other organs.

Companies developing Crispr-based therapies are devoting significant resources to solving the delivery problem. Beam Therapeutics, for example, is investing two-thirds of its “innovation dollars” in the effort, CEO John Evans recently told me. Verve Therapeutics, which aims to apply Beam’s Crispr technology to heart disease, has one-fifth of its team of 150 working on the problem. New biotech companies focused entirely on delivery are expected.

Doudna believes they will find more than one solution. “I’m an optimist,” she says. “There’s a lot of motivation for this challenge to be met.”

A More Precise Toolkit

Crispr’s potential rests in its presumed ability to precisely manipulate DNA — to snip out, repair or even paste in new gene sequences. But it hasn’t yet been refined to do all of these things. The original Crispr-Cas9 tool works best at turning genes off (and sometimes on). That’s wonderfully useful, but also akin to having a word processor with only a “delete” key. In the past decade, the family of Crispr gene editors has expanded to include tools that can swap out individual letters in the genetic code, or even make multiple small edits or additions to that code. Still other tools have emerged that are more efficient at editing, or can be more easily packaged inside the virus or lipid carrier shells.

“What’s still hard to do is get the precision of editing correct,” Doudna says. That is, “having the exact chemical change that you want to occur happening in every cell that gets edited.”

This degree of control matters both for making the edits needed to tackle a broader range of diseases and for making sure there are no unwanted edits that might damage otherwise healthy DNA.

Doudna believes that greater precision will require not only creating more tools but also going back to basic biology to better understand things like how cells respond to DNA repair and the interactions among genes.

Focus

CRISPR

Client

Doudna/IGI

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