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Gene-Editing Advance Puts More Gene-Based Cures Within Reach

Posted on by Dr. Francis Collins

Prime Editing
Caption: The prime editing system (left) contains three parts: two enzymes, Cas9 and reverse transcriptase, and an engineered guide RNA, pegRNA. Unlike regular CRISPR gene editing, prime editing nicks just one strand of the DNA molecule (right) and then uses RNA and reverse transcriptase to direct highly targeted changes to a cell’s DNA. Credit: Broad Institute of MIT and Harvard, Cambridge, MA.

There’s been tremendous excitement recently about the potential of CRISPR and related gene-editing technologies for treating or even curing sickle cell disease (SCD), muscular dystrophy, HIV, and a wide range of other devastating conditions. Now comes word of another remarkable advance—called “prime editing”—that may bring us even closer to reaching that goal.

As groundbreaking as CRISPR/Cas9 has been for editing specific genes, the system has its limitations. The initial version is best suited for making a double-stranded break in DNA, followed by error-prone repair. The outcome is generally to knock out the target. That’s great if eliminating the target is the desired goal. But what if the goal is to fix a mutation by editing it back to the normal sequence?

The new prime editing system, which was described recently by NIH-funded researchers in the journal Nature, is revolutionary because it offers much greater control for making a wide range of precisely targeted edits to the DNA code, which consists of the four “letters” (actually chemical bases) A, C, G, and T [1].

Already, in tests involving human cells grown in the lab, the researchers have used prime editing to correct genetic mutations that cause two inherited diseases: SCD, a painful, life-threatening blood disorder, and Tay-Sachs disease, a fatal neurological disorder. What’s more, they say the versatility of their new gene-editing system means it can, in principle, correct about 89 percent of the more than 75,000 known genetic variants associated with human diseases.

In standard CRISPR, a scissor-like enzyme called Cas9 is used to cut all the way through both strands of the DNA molecule’s double helix. That usually results in the cell’s DNA repair apparatus inserting or deleting DNA letters at the site. As a result, CRISPR is extremely useful for disrupting genes and inserting or removing large DNA segments. However, it is difficult to use this system to make more subtle corrections to DNA, such as swapping a letter T for an A.

To expand the gene-editing toolbox, a research team led by David R. Liu, Broad Institute of MIT and Harvard, Cambridge, MA, previously developed a class of editing agents called base editors [2,3]. Instead of cutting DNA, base editors directly convert one DNA letter to another. However, base editing has limitations, too. It works well for correcting four of the most common single letter mutations in DNA. But at least so far, base editors haven’t been able to make eight other single letter changes, or fix extra or missing DNA letters.

In contrast, the new prime editing system can precisely and efficiently swap any single letter of DNA for any other, and can make both deletions and insertions, at least up to a certain size. The system consists of a modified version of the Cas9 enzyme fused with another enzyme, called reverse transcriptase, and a specially engineered guide RNA, called pegRNA. The latter contains the desired gene edit and steers the needed editing apparatus to a specific site in a cell’s DNA.

Once at the site, the Cas9 nicks one strand of the double helix. Then, reverse transcriptase uses one DNA strand to “prime,” or initiate, the letter-by-letter transfer of new genetic information encoded in the pegRNA into the nicked spot, much like the search-and-replace function of word processing software. The process is then wrapped up when the prime editing system prompts the cell to remake the other DNA strand to match the new genetic information.

So far, in tests involving human cells grown in a lab dish, Liu and his colleagues have used prime editing to correct the most common mutation that causes SCD, converting a T to an A. They were also able to remove four DNA letters to correct the most common mutation underlying Tay-Sachs disease, a devastating condition that typically produces symptoms in children within the first year and leads to death by age four. The researchers also used their new system to insert new DNA segments up to 44 letters long and to remove segments at least 80 letters long.

Prime editing does have certain limitations. For example, 11 percent of known disease-causing variants result from changes in the number of gene copies, and it’s unclear if prime editing can insert or remove DNA that’s the size of full-length genes—which may contain up to 2.4 million letters.

It’s also worth noting that now-standard CRISPR editing and base editors have been tested far more thoroughly than prime editing in many different kinds of cells and animal models. These earlier editing technologies also may be more efficient for some purposes, so they will likely continue to play unique and useful roles in biomedicine.

As for prime editing, additional research is needed before we can consider launching human clinical trials. Among the areas that must be explored are this technology’s safety and efficacy in a wide range of cell types, and its potential for precisely and safely editing genes in targeted tissues within living animals and people.

Meanwhile, building on all these bold advances, efforts are already underway to accelerate the development of affordable, accessible gene-based cures for SCD and HIV on a global scale. Just last month, NIH and the Bill & Melinda Gates Foundation announced a collaboration that will invest at least $200 million over the next four years toward this goal. Last week, I had the chance to present this plan and discuss it with global health experts at the Grand Challenges meeting Addis Ababa, Ethiopia. The project is an unprecedented partnership designed to meet an unprecedented opportunity to address health conditions that once seemed out of reach but—as this new work helps to show—may now be within our grasp.


[1] Search-and-replace genome editing without double-strand breaks or donor DNA. Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, Chen PJ, Wilson C, Newby GA, Raguram A, Liu DR. Nature. Online 2019 October 21. [Epub ahead of print]

[2] Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Nature. 2016 May 19;533(7603):420-424.

[3] Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR. Nature. 2017 Nov 23;551(7681):464-471.


Tay-Sachs Disease (Genetics Home Reference/National Library of Medicine/NIH)

Sickle Cell Disease (National Heart, Lung, and Blood Institute/NIH)

Cure Sickle Cell Initiative (NHLBI)

What are Genome Editing and CRISPR-Cas9? (National Library of Medicine/NIH)

Somatic Cell Genome Editing Program (Common Fund/NIH)

David R. Liu (Harvard, Cambridge, MA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; National Institute for General Medical Sciences; National Institute of Biomedical Imaging and Bioengineering; National Center for Advancing Translational Sciences

Joining Forces Against Sickle Cell Disease and HIV Infection

Posted on by Dr. Francis Collins

Gates Collaboration Telebriefing
The NIH and the Bill and Melinda Gates Foundation, Seattle, will invest at least $200 million over the next four years to develop affordable gene-based cures globally for sickle cell disease and HIV infection. The announcement of this timely collaboration was made during a late-morning telebriefing at NIH on October 23, 2019. Here, I met with two of my fellow participants on the call: Gary Gibbons (left), director of NIH’s Heart, Lung, and Blood Institute; and Trevor Mundel, (middle), president of the Gates Foundation’s global health efforts. Also joining the telebriefing remotely by phone were Tony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases; and Matishidiso Moeti, director of the World Health Organization’s Regional Office for Africa. Credit: NIH

Milken Global Conference 2019

Posted on by Dr. Francis Collins

Health leaders join hands with Michael Milken
Joining hands with my fellow panelists and host of the Milken Institute Global Conference—Toward a Healthier Future. Our wide-ranging panel discussion focused on some of the major health care issues now before us in prevention, treatment, and care. Standing next to me (from left to right) are: Susan Desmond-Hellmann, chief operating officer of the Bill & Melinda Gates Foundation, Seattle; Tanisha Carino, executive director, FasterCures, Washington, D.C.; Seema Verma, administrator, Centers for Medicare and Medicaid Services, Department of Health and Human Services, Washington, D.C.; Michael Milken, chairman, Milken Institute, Santa Monica, CA; Bernard Tyson, chairman and chief operating officer of Kaiser Permanente, Oakland, CA. Our panel discussion took place on April 29 at the start of the Milken Institute Global Conference 2019 in Beverly Hills, CA. Credit: Centers for Medicare and Medicaid Services.

A Warm Welcome to African Fellows

Posted on by Dr. Francis Collins

I took part in the orientation session for the new African Postdoctoral Training Initiative (APTI) on February 28, 2019. The session was held at the Fogarty Stone House on the NIH campus, and afterwards I joined this inaugural group of APTI fellows and event organizers for a group photo. The orientation, which provided an overview of APTI and its vision to help early-career researchers from Africa excel, was hosted by NIH and its partners in this initiative, the Bill and Melinda Gates Foundation and the African Academy of Sciences. The fellows hail from six African countries, and they will work over the next few years in 10 NIH labs in Maryland, North Carolina, and Montana. Credit: Marleen Van den Neste.

Workshop on Global Health

Posted on by Dr. Francis Collins

Francis Collins walking with Bill Gates and Tony Fauci
The NIH teamed with the Bill Gates and Melinda Gates Foundation to hold their fifth annual consultative workshop on global health. The workshop took place on December 11, 2018 in Bethesda, MD. Some of the topics discussed were a universal flu vaccine, tuberculosis, HIV/AIDS, malaria, and maternal, neonatal and child health. Here, I am heading to the workshop with Bill Gates (left) and Tony Fauci (far left), director of NIH’s National Institute of Allergy and Infectious Diseases. Credit: NIH

How to Make Biopharmaceuticals Quickly in Small Batches

Posted on by Dr. Francis Collins

Diagram showing three components of InSCyT system

Caption: InSCyT system. Image shows (1) production module, (2) purification module, and (3) formulation module.
Credit: Felice Frankel Daniloff, Massachusetts Institute of Technology, Cambridge

Today, vaccines and other protein-based biologic drugs are typically made in large, dedicated manufacturing facilities. But that doesn’t always fit the need, and it could one day change. A team of researchers has engineered a miniaturized biopharmaceutical “factory” that could fit on a dining room table and produce hundreds to thousands of doses of a needed treatment in about three days.

As published recently in the journal Nature Biotechnology, this on-demand manufacturing system is called Integrated Scalable Cyto-Technology (InSCyT). It is fully automated and can be readily reconfigured to produce virtually any approved or experimental vaccine, hormone, replacement enzyme, antibody, or other biopharmaceutical. With further improvements and testing, InSCyT promises to give researchers and health care providers easy access to specialty biologics needed to treat rare diseases, as well as treatments for combating infectious disease outbreaks in remote towns or villages around the globe.

Gene Drive Research Takes Aim at Malaria

Posted on by Dr. Francis Collins

Mosquitoes and a Double HelixMalaria has afflicted humans for millennia. Even today, the mosquito-borne, parasitic disease claims more than a half-million lives annually [1]. Now, in a study that has raised both hope and concern, researchers have taken aim at this ancient scourge by using one of modern science’s most powerful new technologies—the CRISPR/Cas9 gene-editing tool—to turn mosquitoes from dangerous malaria vectors into allies against infection [2].

The secret behind this new strategy is the “gene drive,” which involves engineering an organism’s genome in a way that intentionally spreads, or drives, a trait through its population much faster than is possible by normal Mendelian inheritance. The concept of gene drive has been around since the late 1960s [3]; but until the recent arrival of highly precise gene editing tools like CRISPR/Cas9, the approach was largely theoretical. In the new work, researchers inserted into a precise location in the mosquito chromosome, a recombinant DNA segment designed to block transmission of malaria parasites. Importantly, this segment also contained a gene drive designed to ensure the trait was inherited with extreme efficiency. And efficient it was! When the gene-drive engineered mosquitoes were mated with normal mosquitoes in the lab, they passed on the malaria-blocking trait to 99.5 percent of their offspring (as opposed to 50 percent for Mendelian inheritance).