Breaking new ground: CRISPR

The gene editing technique CRISPR has been heralded for its ability to remove part of a genome while leaving the rest intact. Using an enzyme called a nuclease, such as Cas9 (that comes from bacteria), CRISPR cuts DNA in a specific spot using a short piece of RNA called guide RNA.

Spanish professor Francisco Mojica, at the University of Alicante in Spain, was the scientist who discovered the mechanism at the core of CRISPR (1993) and the person who gave the tool its name. When the 2020 Nobel Prize was awarded for the discovery of the CRISPR/Cas9 genetic scissors to Emmanuelle Charpentier and Jennifer Doudna, members of the Nobel Committee for Chemistry noted that the world was just beginning to see the range of applications for which CRISPR could be used. “This enzyme system [CRISPR/Cas9], which utilizes a very delicate and targeted mechanism to cleave DNA and insert new DNA parts, holds enormous power that affects us all,” stated the Committee.

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Quick, cheap and relatively easy

Scientists today can use CRISPR to match a specific DNA sequence in the genome and when the guide RNA latches on to the target DNA sequence, the Cas9 (or another enzyme) is drawn to the designated spot. This enables researchers to edit the genome in the desired sequence. Researchers can permanently modify genes in living cells and organisms to correct mutations at precise locations in the human genome and thus treat genetic causes of disease. 

CRISPR hence makes it possible to correct errors in the genome and turn on or off genes in cells and organisms quickly, cheaply and with relative ease, states the U.S. National Library of Medicine’s National Center for Biotechnology Information. 

Not modifying – editing

Since the idea of cutting genes is unsettling for some, scientists stress that CRISPR does not modify a genome, it edits it, states Monika Paulé, CEO of Lithuania-based Caszyme, a company that provides CRISPR solutions for its clients. “We’re working with the same organism,” she says.

Now we can make this process more effective and targeted.

Many people don’t realize that some level of gene editing has been taking place for years, particularly in the field of natural breeding agriculture, where plants adapt to environmental conditions to grow bigger or hardier crops. “Now we can make this process more effective and targeted,” explains Paulé. “We work with different industries, such as agritech, therapeutics, research tools, and diagnostics, and with the whole spectrum of business partners.”

Monika Paulé, CEO, Caszyme

Founded by scientists who were among the pioneers who demonstrated that CRISPR/Cas9 can generate precise double-stranded DNA breaks, Caszyme has helped to usher in a new era of gene editing. Their work includes developing novel CRISPR solutions for personalized medicine using precise and specific interventions to treat and cure genetic and acquired diseases. The company provides clients access to mRNA synthesis, proteins characterization, and analysis and potency testing for early-stage CRISPR discovery.

“We do this early-stage CRISPR research and development and discover novel Cas proteins,” Paulé says. “If the company doesn’t have gene editing capabilities or needs more expertise, if they face challenges in their gene editing research and development, we can help.”

Shred the DNA like a real Pac-Man

One particularly intriguing application of CRISPR/Cas is its potential to treat genetic disorders that are the result of a single gene mutation. These diseases include cystic fibrosis (CF), Duchenne’s muscular dystrophy (DMD), and haemoglobinopathies. The approach has worked in preclinical models. CRISPR can also be used to treat cancer by singling out the cancer cells instead of all the cells in the area.

“You can eliminate one harmful bacterium and keep the good ones,” says Christian Grøndahl, co-founder and CEO of the Danish company SNIPR Biome. “We’ve been able to kill whatever bacteria we tried it on in the lab. We want to turn the technology into a drug and the best outcome would be if we could treat indications and diseases that cannot be treated right now.”

SNIPR’s primary goal is to engineer microbiomes using CRISPR technology to treat several serious and life-threatening diseases, ranging from irritable bowel disease (IBD) to multi drug-resistant infections and cancer. Finding new ways to combat antibiotic resistant bacteria is also a high priority for Grøndahl and his colleagues.

“We’re really behind the curve when it comes to medicines, we take antibiotics for granted,” he says, referring to society as a whole. “There has been a 30-year gap with no new antibiotics. Why aren’t we investing in that? Between 10 to 20 percent of all cancer patients die of infections we cannot treat, and governments and agencies are starting to realize that more people are dying from antibiotic resistance. There are five or six bacteria that are resistant to antibiotics. We hope to bring new medicines to society,” emphasizes Grøndahl.

SNIPR Biome uses a different class of CRISPR systems, called the CRISPR/Cas3. “Instead of just making a double-stranded break like Cas9, Cas3 can actually shred the DNA like a real Pac-Man,” he says.

Recently the company also discovered its own CRISPR/Cas system which they call CasS, which is even smaller than CRISPR/Cas3, says Grøndahl.

Precise changes in genes

Precision killing of bacteria has the potential to revolutionize the management of untreatable and difficult-to-treat conditions as well as complex diseases directly impacted by the human microbiota, according to Christian Grøndahl. “We do not merely use CRISPR as a tool, it is at the core of the drugs we make,” he says. “The CRISPR system is specifically programmed to remove the harmful components out of the microbiome while retaining the beneficial microbes.”

“We focus on indications with a high unmet medical need,” he continues. “In the western world this means removing E. coli from the gut of hematological cancer patients as they are the group at a higher risk of blood stream infections. Additionally, we work successfully with the Bill & Melinda Gates Foundation to target EED [environmental enteric dysfunction] in the global south.”

Genes are in bacteria, man, mice, and plants, and CRISPR is a natural mechanism that allows precise changes in genes.

The company currently has one drug (SNIPR001) designed to target E. coli infections in patients with blood cancer. They have completed Phase 1 of a clinical trial in the US and have now moved into Phase 1b/2a at stem-cell transplantation centers in the US.

Grøndahl’s hope for the future is that not only will CRISPR’s uses expand, the public’s understanding and appreciation of its capabilities will also grow.

“I want people to embrace the fact that genes are not scary, that there is nothing unnatural about them,” he says. “We’ve been modifying genes for decades, we’ve been modifying genes for livestock and production. Everything living contain genes. Genes are in bacteria, man, mice, and plants, and CRISPR is a natural mechanism that allows precise changes in genes.”