Potentially Hazardous: CRISPR Therapeutics Could Promote Cancer

The CRISPR genome editing technique is incredibly efficient but not necessarily secure, the researchers warn. Sometimes cleaved chromosomes do not regrow, compromising genomic stability, which over time might support cancer.

According to recent research from Tel Aviv University, using CRISPR therapeutics, a breakthrough, Nobel Prize-winning approach that entails cleaving and editing DNA, to treat ailments including cancer, liver, and intestinal disorders, and genetic abnormalities, has risks. Up to 10% of the treated T-cells, which are white blood cells in the immune system, had genetic material destroyed, according to research on how this procedure affected them. They clarify that such loss might cause the genome to become unstable, which might cause cancer.

The Tel Aviv Sourasky Medical Center (Ichilov) and Tel Aviv University collaborated on the study, which was led by Dr. Adi Barzel of TAU's Wise Faculty of Life Sciences and Dotan Center for Advanced Therapies, as well as Drs. Asaf Madi and Uri Ben-David of TAU's Faculty of Medicine and Edmond J. Safra Center for Bioinformatics. The study was just released in the esteemed scientific publication Nature Biotechnology.

In dividing cells, chromosome segregation occurs. Red represents the cell cytoskeleton, blue represents DNA, and green represents a protein that identifies dividing cells. Credit goes to Ben David Lab and Tom Winkler.

The cutting-edge DNA editing method CRISPR cleaves DNA sequences at particular sites to remove undesirable segments, repair damaged segments, or add helpful segments. The technique, which was created about ten years ago, has already shown promise in the treatment of a number of diseases, including cancer, liver illness, genetic syndromes, and more.

In 2020, researchers at the University of Pennsylvania used CRISPR to modify T-cells, which are immune system's white blood cells, in the first allowed clinical study to do so. Scientists built a receptor that targets cancer cells using T-cells from a donor while utilizing CRISPR to eliminate the genes encoding for the original receptor, which would have caused the T-cells to attack cells in the recipient's body.

Assuming that damaged DNA cannot always be repaired, the goal of the current investigation was to determine if the potential advantages of CRISPR treatments would be outweighed by hazards stemming from the cleavage itself.

The genome in our cells frequently breaks owing to natural causes, but most of the time it is able to repair itself, with no harm done, according to Dr. Ben-David and his research assistant Eli Reuveni. However, occasionally a particular chromosome is unable to recover, leading to the loss of substantial portions or perhaps the entire chromosome. These chromosomal alterations can cause the genome to become unstable, and cancer cells frequently exhibit this. Therefore, CRISPR therapies, in which DNA is purposefully cut as a means of treating cancer, may, in unlikely circumstances, actively encourage cancers.

The scientists carried out a repeat of the 2020 Pennsylvania experiment, cleaving the T-cells' genome at the exact same places—chromosomes 2, 7, and 14 (of the human genome's 23 pairs of chromosomes)—to assess the possible level of damage. They examined each cell separately and evaluated the amounts of each chromosome's expression using single-cell RNA sequencing, a cutting-edge technique.                                                                                                            

In several of the cells, a sizable loss of genetic material was thus discovered. For instance, roughly 5% of the cells had little to no expression of Chromosome 14 after it had been cleaved. The damage exacerbated when all the chromosomes were cut at once, and just 9%, 10%, and 3% of the cells were able to patch up the breaks in chromosomes 14, 7, and 2, respectively. However, the degree of the damage suffered by the three chromosomes varied.

"Single-cell RNA sequencing and computational analysis enabled us to acquire very exact results," said Dr. Madi and his student Ella Goldschmidt. We discovered that the precise location of the cleaving on each of the three chromosomes was the reason for the difference in damage. Overall, our research shows that the CRISPR-edited T-cells had lost a sizable amount of genetic information in over 9% of the cases. Such a loss may cause the genome to become unstable, which may encourage the development of cancer.

The researchers advise employing CRISPR therapies with extreme caution in light of their findings. They also recommend further study into two different types of potential solutions: reducing the production of damaged cells or identifying damaged cells and removing them prior to the material being administered to the patient. They also offer substitute, less risky methods for particular medical procedures.

In their conclusion, Dr. Barzel and his Ph.D. student Alessio Nahmad write: "Our goal with this work was to raise awareness of potential hazards associated with the use of CRISPR therapies. Even though we are aware of the technology's significant benefits, we nonetheless did this. In fact, we have created CRISPR-based therapies in other research, including a promising AIDS therapeutic. We even started two businesses, one of which employs CRISPR technology and the other of which purposefully does not. In other words, we develop this incredibly useful technology while also highlighting its possible risks. Although it may sound contradictory, we scientists are extremely proud of our method since we think that not taking sides is the very heart of research. We investigate both the good and negative elements of a problem in an effort to find solutions.

By TEL-AVIV UNIVERSITY