Expanding CRISPR’s Potential – What Is CRISPR and Why It Matters
Since its discovery, CRISPR (“Clustered Regularly Interspaced Short Palindromic Repeats”), which won the 2020 Nobel Prize in Chemistry, has revolutionized medicine and biotechnology.
Source: Nobel Prize
This is because CRISPR is the first method for gene editing that allows for very precise targeting of a specific genetic sequence, allowing for correcting genetic errors either in vitro or in vivo without risking unwanted mutations.
This is important as undirected gene insertion has been linked to major problems, notably cancer risks, making their therapeutic use difficult and controversial.
CRISPR can be used in multiple ways to interrupt a gene already present, delete a specific sequence, or edit/insert the right genetic sequence.
Source: CRISPR Therapeutics
This turned into a medical breakthrough with the FDA approval for the first CRISPR-based therapy in 2023, developed by CRISPR Therapeutics (CRSP -2.34%) for genetic blood diseases (follow the link for a dedicated report about CRISPR Therapeutics).
However, human-controlled precise gene editing is not what CRISPR was used for in nature. This is, first and foremost, an antiviral tool that bacteria use to survive attacks from viruses.
And it now appears that CRISPR is even more versatile than previously understood, as it can modify a cell metabolism, blocking viral replication. This was a discovery made by five researchers at the Rockefeller University and the Memorial Sloan Kettering Cancer Center.
They published their results in the prestigious scientific magazine Science1, under the title “Cat1 forms filament networks to degrade NAD+ during the type III CRISPR-Cas antiviral response”.
CRISPR’s Natural Origins in Bacteria
Most bacteria are under constant threat of viruses specialized in attacking them, called bacteriophages (literally named “bacteria eaters”).
For that matter, this is why these phages are currently being investigated for their potential in forming “living antibiotics” that would bypass most of the growing antibiotic resistances.
Each CRISPR genetic sequence found within an individual bacterial CRISPR is derived from a DNA fragment of a bacteriophage that had previously infected the prokaryote or one of its ancestors.
These sequences are used to detect and destroy DNA from similar bacteriophages during subsequent infections, forming a sort of “acquired immunity” against phages. CRISPR is found in approximately 50% of sequenced bacterial genomes.
Considering how widespread CRISPR systems are, and how important they are against viral infections or bacteria, it is maybe not so surprising that they have other additional antiviral properties.
CRISPR Can Block Viruses by Halting Cell Function
CRISPR As Bacteria’s Collective Immune System
Other activities than “genetic scissor” for CRISPR systems are increasingly well understood, notably thanks to the effort of the Rockefeller’s Laboratory of Bacteriology headed by Pr. Luciano Marraffini.
Source: Amacad
They focused especially on a class of molecules in CRISPR-Cas10 systems called CARF effectors, which are proteins that are activated upon phage infection of a bacterium.
CARF effectors have different multiple approaches to reach the same goal: stop cellular activity. As DNA replication and protein production stop in the infected cells, so does the virus production.
“The collective work of our labs is revealing just how effective—and different—these CARF effectors are. The range of their molecular activities is quite amazing.”
Pr. Luciano Marraffini – Rockefeller’s Laboratory of Bacteriology
This effect indirectly protects all the other bacteria in the area and is ultimately quite similar in its principles to mammals’ immune system lymphocytes NK (Natural Killer) that killed infected cells (and cancer cells) to stop the virus propagation.
Cat1 Protein: The Key to CRISPR’s New Trick
Like for many recent biotech discoveries, advanced AI tools came to help the researchers in finding a needle in a hay stack. In this case, it was a tool called Foldseek, a search program based on Google’s (GOOGL +4.48%) AlphaFold tool to predict 3D configuration of proteins.
Instead of comparing protein sequences, Foldseek compares their 3D structure, increasing the chance of finding proteins that are functionally similar, even if using a different amino acid sequence. Foldseek decreases computation times by four to five orders of magnitude compared to previous methods.
Source: ResearchGate
With Foldseek, the researchers found a protein likely to be CARF effector that they called Cat1, which proved to have a very precise activation system.
This protein is alerted to a virus’ presence by secondary messenger molecules called cyclic tetra-adenylate, or cA4. It then makes Cat1 breakdown an essential metabolite in the cell called NAD+.
“Once a sufficient amount of NAD+ is cleaved, the cell enters a growth-arrest state.
With cellular function on pause, the phage can no longer propagate and spread to the rest of the bacterial population.”
Christian Baca – TPCB graduate student.
What the Structure of Cat1 Reveals
As often, the more scientific discoveries are made, the more new questions arise as well.
When studying the actual structure of Cat1, the researchers found that it has an odd shape.
Double copies of Cat1 are glued by cA4 signal molecule, forming long filaments upon viral infection, and trap the NAD+ metabolites within sticky molecular pockets. It even formed more complex structures at the cellular level.
“The filaments interact with each other to form trigonal spiral bundles, and these bundles can then expand to form pentagonal spiral bundles,”
Puja Majumder – Postdoctoral research scholar in the Patel Lab
Source: Rockefeller’s Laboratory of Bacteriology
Could These Antiviral Tricks Work in Humans?
The very complex and wide range of antiviral capacities of CRISPR systems in bacteria beg a question: Could this work for humans as well?
This is of course an idea that has been discussed already, especially as viruses are still much harder to fight forms of infection than bacteria, for which antibiotics are (still mostly) effective.
One such possibility would be genome editing to treat chronic viral infections like HIV, SARS-CoV-2, and hepatitis viruses. Viruses like smallpox and monkeypox could also maybe be treated this way.
This higher level of understanding of CRISPR systems could also help add functionalities or reduce side effects of existing CRISPR-based gene therapy, making them an even better therapeutic tool.
Investing in CRISPR Technologies
CRISPR Therapeutics
CRISPR Therapeutics AG (CRSP -2.34%)
What sets CRISPR Therapeutics apart is the all-star team of founders, which includes Dr. Emmanuelle Charpentier, whose seminal research unveiled the key mechanisms of the CRISPR-Cas9 technology.
It laid the foundation for the use of CRISPR-Cas9 as a versatile and precise gene-editing tool. Numerous awards have recognized her work, including the 2020 Nobel Prize in Medicine and the Breakthrough Prize in Life Science.
CRISPR Therapeutics is developing an efficient and versatile CRISPR/Cas9 gene-editing platform for therapies to treat hemoglobinopathies, cancer, diabetes, and other diseases.
The first therapy that they were advancing was targeting the blood diseases β-thalassemia and sickle cell disease.
They have now been approved under the commercial name of Casgevy for both applications. The company’s first allogeneic CAR-T program targeting B-cell malignancies is also in clinical trials.
While sickle cell is a disease with an arguably small market, once the technology is mature they can advance to targeting other disease vectors.
As the first company with an approved CRISPR therapy, CRISPR Therapeutics is in a good position to be the first to generate positive cash flow from the technology and expand its applications further.
And this stellar track record will likely make the company a partner of choice for any other pharmaceutical company looking to catch up in CRISPR therapies.
Latest CRISPR Therapeutics (CRSP) Stock News and Developments
Study Referenced:
1. Christian F. Baca et al. Cat1 forms filament networks to degrade NAD+ during the type III CRISPR-Cas antiviral response. Science 10 Apr 2025. DOI: 10.1126/science.adv9045