Gene editing has played a pivotal role in uncovering a long-standing mystery about cancer, confirming the suspicions of scientists from over a hundred years ago. The research, recently published in the esteemed journal Science, renews scientific interest in an age-old concept that could potentially pave the way for innovative methods to target cancer cells with the aid of pharmaceuticals.
During the early 1900s, while scrutinizing cancer cells under microscopes, scientists made a groundbreaking observation. They noticed that as cancer cells multiplied, some acquired an excessive number of chromosomes, which are now understood to carry genes. On the other hand, certain cells ended up with an insufficient number of chromosomes.
These astonishing findings led a German embryologist to suggest that abnormal numbers of chromosomes might not only be a characteristic feature of cancer but could potentially be the cause of it. However, as researchers began to discover numerous individual genes responsible for cancer and developed drugs to target them, this idea gradually lost favor.
Nevertheless, the chromosomal irregularities in cancer cells remained an intriguing anomaly—present in 90 percent of all cancers—yet the reason behind their existence and their significance remained largely unknown. “To some extent, it was overlooked due to the sheer challenge associated with its study,” explains Uri Ben-David, an associate professor of human molecular genetics and biochemistry at Tel Aviv University, who was not involved in the recent study. “For many decades, it was kind of ignored. It was like an elephant in the cancer research room.”
In this new study, scientists have managed to tackle this mystery by employing a clever CRISPR technique. Their work demonstrates that certain cancer cells, devoid of additional chromosomes, lose the ability to initiate tumor growth in animals.
Determining the Role of Chromosomal Abnormalities
Humans possess 23 pairs of chromosomes, threadlike structures composed of DNA and protein that carry our genetic information. Normally, during cell division, chromosomes replicate themselves and then separate neatly and symmetrically into new cells. However, in cancer, this process goes awry, resulting in cells possessing abnormal numbers of chromosomes.
For decades, researchers grappled with a perplexing question: were these chromosomal aberrations the cause of cancer or merely a consequence of the cell’s disarray? At the time, manipulating chromosomes was challenging, making it difficult for scientists to find answers, forcing them to rely on intriguing correlations.
One study exposed melanoma cells to a chemical that further disrupted their chromosomes, and researchers discovered that these cells became more resistant to targeted drugs. This finding hinted that chromosomal abnormalities might play a role in cancer’s ability to thwart therapeutic interventions. Another study revealed that patients with highly chromosomally unstable tumor cells exhibited aggressive cancer and a poorer prognosis.
Yet again, the question of cause and effect lingered: were chromosomal disruptions contributing to these cancers or were they merely downstream effects?
The advent of CRISPR gene editing technology a decade ago provided scientists with the ability to add, remove, or modify genes. However, deleting an entire chromosome posed a new challenge. To achieve comprehensive chromosome engineering, Jason Sheltzer, a cancer biologist at Yale School of Medicine, and his team devised a CRISPR technique. Initially, they inserted a gene from the herpes virus onto the extra chromosomes of a cancer cell. Specifically, they targeted chromosome 1q, which is one of the chromosomes that often gain or lose additional copies during the development of breast cancer.
Next, the researchers employed a herpes treatment called ganciclovir to target the modified chromosomes. This technique resulted in the elimination of cells with extra copies, leaving behind cancer cells with a normal number of chromosomes.
When attempts were made to grow tumors using this subpopulation of cancer cells, it was discovered that these cells could no longer initiate tumor formation, whether in a petri dish or live mice. Sheltzer interprets this as definitive evidence that the presence of extra chromosomes is not just an effect but a driver of the disease itself.
“It has a central role,” emphasizes Sheltzer.
Novel Approaches to Combat Cancer
Currently, this technique serves as a tool rather than a therapy. Restoring a normal number of chromosomes in cancer cells to prevent the disease is not yet a feasible option. However, it does offer a fresh perspective on future strategies for targeting cancer. The understanding of the genetic aspects of cancer has led to therapies that specifically target mutations responsible for driving its progression. Nevertheless, cancer is an elusive adversary and often develops resistance to singular therapeutic approaches.
The realization that extra chromosomes play a critical role in driving cancer opens up a new avenue for researchers: identifying and eliminating cells that harbor additional chromosomes. Since chromosomes house hundreds or even thousands of genes, such an approach could expand the repertoire of therapeutic targets. Even if cancer were to eventually develop “resistance” to a drug by losing its extra chromosomes, the study suggests that this loss might also result in the suppression of its cancer-causing potential.
In essence, the extra chromosome becomes a newfound vulnerability that can be targeted therapeutically. Due to the abundance of genetic material present in such cells, they may become sensitive to drugs that target a particular gene, even if it is unrelated to cancer.
In conclusion, the use of gene editing techniques has shed light on a century-old mystery surrounding cancer. The discovery that extra chromosomes are significant drivers of the disease presents new possibilities for combating cancer and provides a potential breakthrough in the development of future therapies. By unraveling the complexities of chromosomal abnormalities, scientists are paving the way for innovative approaches that may transform our ability to tackle this formidable disease.