All eyes on CRISPR

Few things better encapsulate the dreams of the scientific community or the fears of the public than gene editing. The cutting edge of gene editing technology, CRISPR/Cas9, has gained a reputation as a cheap, powerful and easy-to-use tool, sparking a national debate in the process.

On the one hand, the possibility of curing hundreds of formerly untreatable conditions affecting billions worldwide, potentially with just a one-time treatment for each disease, could make death from genetic diseases a thing of the past.

On the other hand, the ability to edit the genome of a human being also could allow for the preferential selection of positive traits and suppression of negative traits in those who can afford to do so, leading to the possibility of so-called “designer babies” and a widening of the gap between socioeconomic classes.

Due to its vast medical potential and simultaneous risk for abuse, there are mixed feelings in the U.S. about the ethics of gene editing. The unsanctioned and illegal use of CRISPR to edit human embryos by Chinese scientist He Jiankui in 2018 was widely publicized and criticized, and although he was removed from his university position and sentenced to prison, his actions caused irreparable harm to the public’s perception of gene editing. While Jiankui’s goal of preventing infection in the children of HIV-positive parents was noble, the scientific community was outraged at the lack of oversight and consent for these experiments.

Although gene editing technology does carry inherent risks and potential for abuse as we have seen, it also confers us with the ability to treat or cure diseases that previously carried a death sentence. However, to explore the incredible medical potential of gene editing, we first have to understand the history and science behind the technology. 

"Although gene editing technology does carry inherent risks and potential for abuse as we have seen, it also confers us with the ability to treat or cure diseases that previously carried a death sentence."

-- Gavin Scheldrup

Gene editing is based on the unique ability of a small family of proteins, called restriction enzymes, to cut and destroy specific segments of DNA. Restriction enzymes were first discovered and described in the 1960s, and their discovery laid the groundwork for the field of gene editing to arise. The first instance of de facto gene editing was the 1971 creation of recombinant DNA from two viruses of different species, which quickly led to an explosion in research in the field. Then, 1981 saw the creation of transgenic mice, marking the first instance of genetically modified animals capable of passing the modification to their offspring.

Each paper published and each study conducted using gene editing technology helped to advance our collective knowledge, inch-by-inch, until the revolutionary 2012 discovery that would forever change the field of biology: CRISPR/Cas9.

CRISPR/Cas9 functions fundamentally as a pair of extremely precise molecular scissors. The Cas9 restriction enzyme is loaded with an RNA molecule that is complementary to the DNA sequence of the targeted gene. Upon injection of Cas9, the enzyme-RNA complex will travel into the nucleus of cells and snip out the DNA sequence it has been programmed to locate. Then, natural cellular DNA repair mechanisms will mobilize to repair the DNA break by joining the two ends together, reforming the continuous strand of DNA, albeit without the targeted gene. Certain modifications to the CRISPR/Cas9 system can also allow for the insertion of new genes or the precise editing of existing ones.

CRISPR/Cas9 is a cheap, intuitive and extraordinarily powerful tool for biomedical research. It has quickly become the gold standard for gene editing and has been used countless times to correct genetic mutations permanently, both in lab-grown cells and in live animals.

Clinical trials in human patients have also shown promising results, suggesting the possibility of CRISPR/Cas9 as the future of modern medicine. Trials are ongoing for dozens of different diseases including macular degeneration, Non-Hodgkin lymphoma and HIV. However, until very recently, CRISPR/Cas9 was not approved by the FDA for use in treating genetic diseases in humans.

On December 8, 2023, the FDA made the monumental decision to approve the use of a CRISPR/Cas9-based drug to treat sickle cell disease in human patients. Sickle cell disease is caused by a single point mutation in the β-globin gene, meaning one letter is changed in the amino acid code for the β-globin protein, which results in abnormal red blood cells with a distinctive sickle shape. Symptoms typically consist of anemia and crises of severe pain, as well as organ damage, stroke and death in severe cases.

The recently approved drug, Casgevy, was created by Vertex Pharmaceuticals and showed dramatic efficacy at functionally curing sickle cell disease in its clinical trial. Of the 31 patients treated with Casgevy during this trial, 29 (93.5%) reported a complete elimination of pain crises—the hallmark symptom of sickle cell disease—during the one-year follow-up window.

Casgevy’s approval by the FDA heralds a new age for gene therapy, as it is surely the first of many CRISPR/Cas9-based treatments that will be approved for use in the coming years. CRISPR/Cas9 represents a profound technological advancement, blurring the lines between science fiction and reality. While the long-term societal impacts of its approval are yet to be seen, many people worldwide will now have access to a life-changing cure for sickle cell disease.

Will this landmark decision by the FDA be enough to sway opinions, or will gene editing remain a hot topic of contention for the American public? Only the future will tell.