A new form of the genome-editing tool CRISPR-Cas9 appears to significantly expand the range of diseases that could be treated with the technology, by enabling scientists to precisely change any of DNA’s four “letters” into any other and insert or delete any stretch of DNA — all more efficiently and precisely than previous versions of CRISPR. Crucially, scientists reported on Monday, it accomplishes all that without making genome-scrambling cuts in the double helix, as classic CRISPR and many of its offshoots do.

News about this “prime editing” began circulating among CRISPR-ites this month, when the inventors unveiled it at a meeting at Cold Spring Harbor Laboratory. Since then, “the excitement has been palpable,” said genetic engineer Fyodor Urnov of the University of California, Berkeley, who was not involved in the research.

“I can’t overstate the significance of this,” he said, likening the creation of ever-more kinds of genome-editing technologies to the creation of superheroes with different powers: “This could be quite a useful Avenger for the genome-editing community, especially in translating basic research to the clinic” to cure diseases ranging from sickle cell to cystic fibrosis.


Prime editing’s inventors, led by David Liu of the Broad Institute of MIT and Harvard and postdoctoral fellow Dr. Andrew Anzalone, say it has the potential to correct 89% of known disease-causing genetic variations in DNA, from the single-letter misspelling that causes sickle cell to the superfluous four letters that cause Tay-Sachs disease. All told, they report making 175 edits in human and mouse cells.

“There are more than 75,000 DNA changes associated with genetic diseases,” Liu told reporters ahead of the online publication in Nature describing prime editors. “Collectively, they cover all of these.”


Prime editing improves on CRISPR-Cas9 (and all of the tweaks researchers have made to it in the last seven years) in several crucial ways, Liu said. It can change any of DNA’s four nucleotides, or “letters” — denoted A, T, C, and G — into any other, a total of 12 possibilities.

One of Liu’s earlier CRISPR inventions, called base editing, can make only four of those changes: C-to-T, T-to-C, A-to-G, and G-to-A. It cannot, for instance, correct the sickle-cell-causing mutation in the hemoglobin gene, which requires changing a T to an A at a precise spot.

“Prime editing,” Urnov said, “is excellent for the repair of [such] point mutations,” which are the cause of some 7,000 inherited genetic diseases.

Unlike other forms of CRISPR, prime editors easily make those repairs in non-dividing cells such as neurons and muscle cells, which genome-editing researchers are eyeing as targets for treating diseases ranging from Duchenne muscular dystrophy to Rett syndrome.

In addition to changing one nucleotide to another, prime editors can remove a precise number of nucleotides from a precise spot in the genome. For instance, the Broad scientists removed (from human cells growing in lab dishes) the four nucleotides in the gene HEXA that cause Tay-Sachs disease. Elsewhere, they were able to remove as many as 80.

“It looks like prime editing will offer some new capabilities to the genome editing community,” said biochemist Benjamin Kleinstiver of Massachusetts General Hospital, whose research centers on turning genome editing into “molecular medicine.”

Most impressive to other scientists is prime editing’s ability to insert missing nucleotides or replace a string of disease-causing ones with nucleotides supplied by CRISPR. Liu and his colleagues inserted as many as 44, a quantity he says they were “skeptical” of achieving. Now, however, he believes “it’s likely that larger insertions, and deletions [greater than 80], would be possible.”

In classic CRISPR, genome editing begins when the Cas9 enzyme cuts DNA at a site to which a target-finding molecule, called guide RNA, led it. That triggers DNA’s natural repair machinery, which can respond in several ways: mending the break by knitting the two loose ends together; filling the gap with nucleotides randomly grabbed from the cell; or patching the break with a piece of repair DNA supplied by scientists. It turns out that cells much prefer the first and second options. That has made the third, called homology-directed repair, very difficult — a real problem since curing many genetic diseases would require this kind of fix.

Prime editing’s ability to get human genomes to accept a repair template was therefore particularly impressive to other scientists, since “no one has found a good way to do it,” Urnov said. In a study that rocked the genome-editing world, for instance, scientists reported in 2017 that human embryos with a gene that causes the heart disease hypertrophic cardiomyopathy rejected the healthy gene that was introduced via CRISPR. Yet using CRISPR to cure cardiomyopathy and some other inherited genetic diseases would likely require homology-directed repair.

Prime editing “works for a whole range of nucleotide changes that may be necessary to correct disease genes,” said Maria Jasin of Memorial Sloan Kettering Cancer Center, an expert in DNA repair. “It is a meaningful advance.”

The molecules that accomplish prime editing’s genetic legerdemain have three parts. A guide RNA, which the Liu team calls pegRNA (where “pe” stands for prime editing), makes a beeline for a pre-programmed spot on the genome. The pegRNA also contains nucleotides that will substitute for the disease-causing ones in the DNA target. The second component, a hobbled Cas9 enzyme, cuts one, but not both, strands of the DNA. The third component, an enzyme called reverse transcriptase that’s fused to Cas9, copies the RNA nucleotides carried by the pegRNA and transforms them into DNA nucleotides, which replace those at the target site.

“The net result is a permanent edit that has been copied from the information encoded in the pegRNA,” Liu said. As for versatility, he and his colleagues used the prime editor to, in one case, precisely delete two DNA nucleotides and, at the same time, convert a G into a T five letters away, “all in one edit” — the genome equivalent of a pool shark’s banking the 9 ball off the 7 and sinking the 1, 5, and 6.

So far, Liu’s team has tested the prime editor on human cells and on mouse neurons. In both, the rate at which unintended spots in the genome were edited was extremely low: rates of such off-target edits were below 10%. Efficiency was high, typically 20% to 50%, depending on the kind of edit, and as high as 78%. Other CRISPR systems struggle to get into the double digits. And only 1% to 10% of prime-edited cells had unwanted insertions or deletions (“indels”) of nucleotides, compared to upwards of 90% for some older CRISPR systems.

Because indels could trigger cancer or other genomic havoc, “avoiding indels in certain gene therapy applications is certainly a big deal,” Jasin said.

One concern that she and other outside scientists raised is that the human cells used to test the prime editor come from cancer. Although this cell line has been used for decades for many non-cancer experiments, it might not be representative of how well the prime editor will do in other human cells. “More work needs to be done in other cell types,” Jasin said.

The Broad has applied for a patent on prime editing, and is already making it freely available to academic and non-profit researchers for non-commercial uses, without requiring a license. Companies may license the technology non-exclusively for research and manufacturing, including for agriculture. But it has given an exclusive license for the commercial development of human therapeutics to Prime Medicine, a new company co-founded by Liu.

For all their versatility, it’s far from a given that prime editors will take over the CRISPR landscape. For both basic research and therapeutic uses, classic CRISPR (where the intellectual property ownership is spread around broadly) might work just fine. For instance, treating sickle cell requires that a mere 10% of red blood cells have healthy hemoglobin, which seems well within the reach of classic CRISPR.

Similarly, if the clinical trials currently underway using first-generation CRISPR technology to treat a form of congenital blindness (by Editas Medicine) and sickle cell (by CRISPR Therapeutics) succeed, there is no reason to think they’ll be superseded by prime editing. And Beam Therapeutics, which is developing therapies using base editing and has announced plans to go public (and which Liu also co-founded), could well find that that approach works for the diseases it eventually decides to target. It is also sub-licensing rights to prime editing from Prime Medicine.

Dr. Matthew Porteus of Stanford University, who is leading a clinical trial using CRISPR to cure sickle cell, cautioned that whether prime editing can “solve a problem that can’t be solved by [classic CRISPR] remains to be determined.”

  • Is this article an exercise in how much hyperbole can we possibly fit into one article? I don’t think you quoted enough hypesters and hucksters to really give it that final bit of oomph. When is the next episode of “Fyodor’s Avengers?”

    Meanwhile, the great irony of all this is that the breathless hype and self-promotion coming from the initial batch of CRISPR Cas9 editing by its own inventors and the compliant media already cast CRISPR-Cas9 as a panacea for human kind and an immediate fix, while downplaying all its limitations and problems. All the bluster in this article about how much they’ve improved on it (supposedly) only reveals how unrealistic was the initial Crispr-Cas9 hype.

    So it leaves the reader wondering, how seriously should I consider THIS new hype for Crispr Prime? Fool me once, shame on you… You ain’t gonna fool me again Fyodor

  • Not all diseases, or even the majority of them are due to “DNA-Glitches” — whatever those might be. Crisper tech is over-vaunted and apps for which it actually works will be few and a long time coming.

  • I do not pretend to understand the article on gene splicing.
    Nevertheless, I am awed by the possibilities to help our fellow humans.
    I pray that it will bring peace, hope, and joy to many of the deserving ill people.
    I am grateful for reasonably good health for a man who has lived in excess of 3/4th of a century. We live in amazing times.

  • Let those who want to try this option to cure themselves of an incurable ailment when no other option exists be the trailblazers.
    However. Using it to enhance oneself seems risky

  • I am an Evangelical Christian minister so I will address this from a moral spiritual angle. There is nothing in the scriptures that could remotely be construed to be a prohibition for gene editing as long as it is for purposes of healing. The idea of playing God by healing people is quite ironic. If you look at the gospels Jesus empowered his disciples to heal with the same power he possessed. So in the spirit of the text playing the God who heals is actually a good thing. I do not say this to aggravate you atheists. I understand this perspective is boulderdash to you, however you should not criticize my attempt to calm the concerns of non-naturalistic people pertaining to a this matter.

    • I also believe in Jesus and I believe we are advancing because we were literally created in His image–>we are also capable of ascending to higher orders of being just like Him and we still have the divine spark. I believe when Jesus commanded us to go out and do as He did he was literally commanding us to do what he did-by any means necessary. And science is how we are doing that.

      While atheist scientist may frown on your opinion, quantum science is changing everything we understand, and may someday prove religion and Magick had a core of truth.

      Faith and science are mutually inclusive to the open mind. I like to remind atheist that Gregor Mendel’s pea plants started out in a Catholic school.

  • Human evolution is no longer occurring. As we have increased life spans and decreased infant mortality rates with medical advances, we have decreased the impact of disease and physical conditions to impact birth rates. If someone who is susceptible to a disease doesn’t breed, their genes don’t get passed on.

    Gene manipulation is the only method to help humans evolve and decrease the impact of diseases and disorders. Just as with GMO foods, gene manipulation improves what is already there, it doesn’t put wings on a pig.

    But the ignorant don’t understand that and will fight. Just like they did when telegraph poles were first installed and they were afraid they would fall and hurt people. Those decrying GMO foods and vaccinations will be the first in line to decry new genetic treatments out of the fear that comes with ignorance. And will put countless lives at risk from diseases that could have easily been treated by trying to force governments to ban them.

    I have no issues with someone who doesn’t want to eat GMO foods or use advanced genetic techniques to treat disease. But when they start to impact my right to those products, they are overstepping their bounds.

    • As a someone that majored in Biology and understands GMO, I am completely okay eating GMO foods—>after long term (20+) year studies in small human populations taking into account the effect on the biosphere. Now I would not hesitate to splice myself, because the potential fallout is limited to the subject. But to generalize that people against GMOs would be against human editing is to miss the genius of humanity: we are smarter than you think. It is one thing to risk a population of aging Baby Boomers; it is an entirely different thing to risk destroying our food supply by inadvertently wiping out insects we thought were pest. The long term repercussions of GMOs (in the wild) are unknowable at this point—>not enough data. For all we know the growing political divides happening everywhere could be the result of GMOs or cell phones, but we will never have enough data to analyze that before we fall… societies come and go, but hubris remains.

  • “A new form of the genome-editing tool CRISPR-Cas9 appears to significantly expand the range of diseases that could be treated with the technology…”

    And expand the numerous unintended mutations caused by any type of genome editing.

  • All disease and death originate in and reflect deficiencies of the MIND down from all the generations of humanity, which is immeasurable. Attempting to ‘cure’ them with pills, potions, tinctures and technology is like trying to ‘correct’ pimples by cracking the mirror, or ‘changing’ the rules of chess by moving the figures… (‘Science’ is still building the tower of Babel, never reaching heaven, i. e., the theoretical realm.)

  • My son’s Duchenne Muscular Dystrophy can be cured with this because his mutation is one letter wrong. My son can literally be cured but who knows how long it will take him to receive this 🙏

    • I believe you hit the nail on the head. The ability to alter ourselves puts us in a new level. I believe in God and I also believe Science is His Will. We are advancing because we were created in His image-literally. Soon we will be ready to greet the stars.

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