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  • Sidharth Raghavan

CRISPR: A Double-Edged Sword

Updated: Aug 1, 2021

I. What is CRISPR?


CRISPR - you may have heard about it. It is a gene editing technology that has revolutionized the field of biotechnology in the last decade. The advent of this remarkable tool has brought scientists closer to curing some of the most dreadful diseases, but has also made scientists question its ethics.


CRISPR Gene Editing Credit: National Institutes of Health (NIH)

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats and consists of repeating sequences of DNA found in single-celled organisms that helps them defend against viruses and other foreign invaders, strengthening their immune system. DNA, a form of hereditary information, is used to make proteins. CRISPR sequences code for a protein called Cas-9 which finds and destroys parts of a DNA strand, deactivating a certain enemy gene. In the 1990s, Francisco Mojica, a scientist at the University of Alicante, Spain, discovered CRISPR when examining archaea; he then looked for it in bacteria and found it there as well. Scientists had recognized these repeating sequences prior to Mojica’s discovery; Mojica, however, was the first one who connected them with the immune system.


CRISPR’s first application was in a popular and tasty food: yogurt. Yogurt is made from bacterial cultures. As you might imagine, fermenting infected bacteria can result in the production of potentially fatal products. To ensure that their prized bacterial cultures would not be infected by viruses, scientists at Danisco, a yogurt company, decided to enlist the help of CRISPR sequences. By studying the CRISPR sequences in yogurt bacteria, the scientists realized that the bacteria developed new CRISPR sequences after each virus attack to protect themselves against future attacks. This discovery was pivotal because it demonstrated that scientists could engineer an immunity to a virus not previously encountered by the bacteria by adding specific base pairs to the CRISPR sequence.


In 2012, Jennifer Doudna and Emmanuelle Charpentier, published a paper demonstrating how CRISPR can be adapted to edit genes. Doudna and Charpentier isolated CRISPR in a test tube and transformed it into a system that can be edited to cut out specific sequences in the DNA of other organisms. More specifically, they showed that CRISPR could be edited by using different kinds of RNA molecules, specifically tracrRNA and crRNA. On the other side of the United States, Feng Zhang, a scientist at the Broad Institute, was developing the CRISPR system at roughly the same time. Zhang, however, focused on adapting CRISPR for mammalian cells. By using new techniques to optimize the CRISPR system, Zhang and his lab were able to successfully use CRISPR in human cells.


Credit: The Royal Swedish Academy of Sciences

The race to develop the CRISPR gene editing system was one of the most important and intricate in scientific history. There are still many disputes over when scientists made their discoveries, and there were many legal battles that occurred as a result. Nevertheless, in October of 2020, Jennifer Doudna and Emmanuelle Charpentier were awarded a well-deserved Nobel prize for the CRISPR gene editing technique. It is important to realize that the evolution of CRISPR was much more than a discovery made by two scientists; rather, it was a cascade of brilliant scientific advancements made by many around the world. The weapon was forged, now how can scientists wield it?


II. Wielding a Powerful Weapon to Fight Disease


The CRISPR technique is now being applied to help cure many diseases. In fact, it is already being used in the fight against cancer. Since cancer is a genetic disease, resulting from an abnormality in the DNA, CRISPR can be used to help cure it.


The “CRISPR” immunotherapy works by modifying T cells - fighter cells that live in the immune system. First, scientists add a gene to the T cells that recognizes a molecule on cancer cells called NY-ESO-1. Then, CRISPR is used to three delete genes that limit the T cell’s ability to kill cancer cells. Early findings suggest that this technique yields few side effects and is a viable immunotherapy.


The SARS-CoV-2 Virus. Credit: NIAID

CRISPR is also extremely useful when scientists were looking to detect and cure COVID-19. Last year, CRISPR-based COVID-19 tests were developed. They use the enzyme Cas13a to identify specific RNA sequences that are specific to the ones in SARS-CoV-2, the virus responsible for COVID-19. Furthermore, scientists at Stanford University are building a COVID-19 vaccine that can use CRISPR to “cut, target, and destroy COVID-19 virus and genome”. While the mRNA and viral vector vaccines developed by Pfizer, Moderna, AstraZeneca, and others will play a crucial role in ending the COVID-19 pandemic, CRISPR vaccines could be more effective so it is crucial that we continue to study them.


Credit: National Institutes of Health (NIH)

Sickle cell anemia is an excruciatingly painful genetic disease caused by the deterioration of red blood cells. Researchers, including Jennifer Doudna, at the University of California, Berkeley, found that the mutated gene responsible for sickle cell disease was called beta-globin. They used CRISPR-Cas9 to correct the mutation in the disease by replacing the damaged beta-globin genes with normal ones. This revolutionary therapy works by first taking the patient’s blood stem cells and using electrical pulses to make pores in their cellular membranes. Then, scientists allow CRISPR-Cas9 to enter the newly created pores in the cells. Finally, the engineered stem cells are injected back into the patient. Now, when red blood cells are built from the stem cells, they will not have a defective beta-globin gene.

Following the discovery of the CRISPR gene editing technique, scientists have been scrambling to utilize it to forge new therapies. There are many new treatments that haven’t been discussed, and I am sure that there will be many more to come in the future. What’s certain is that the quantum leaps made by the early CRISPR scientists could save millions of lives in the coming years.


III. The Dark Side of CRISPR


Gene editing allows us to change the very thing that makes people unique: our DNA. Many scientists wonder with good reason: “Are we playing god?”. Probably - we are messing with the very course of evolution. We must tread with extra caution.


Jiankui presenting his work. Credit: The National Academies

One prime example that showcases the immense power of CRISPR was in 2018 when the scientist He Jiankui edited the embryos of two babies. He not only disobeyed the regulations on gene editing put forth by the scientific community, but also lied to the parents of the newborn twins about what he was going to do. While Jiankui's aim was to immunize the babies against HIV via CRISPR, his method of doing so was untested in humans; newborn babies should not be the test subjects in such unprofessional and dangerous antics. As these two children grow, we’ll have to hope that CRISPR has a favorable impact on their health.


In March of 2019, many scientists from around the world joined forces to create a global memorandum on the clinical uses of gene editing on sperm, eggs, and embryos. While Jiankui’s irresponsible actions were the impetus for this statement, many scientists were also worried about the possibility of genetic enhancements for humans. What if people could make themselves stronger or others weaker? What if governments use CRISPR to make their militaries stronger? What’s worrisome is that it was quite simple to use CRISPR gene editing on children. Who will control others from participating in activities similar to Jiankui? It is vital that governments around the world be on the lookout for CRISPR technology and prevent it from being misused.


All is not lost, though. Often, our human features are controlled by many different genes. Targeting every gene responsible for a specific outcome is a hard task. Furthermore, when you delete a gene, other diseases can arise as a result. CRISPR is far from perfect, but it is still crucial that we keep a keen eye on it as it is being increasingly used as a medical tool.


IV. Conclusion


Mojica's discovery of CRISPR has paved the way for a new era of science: genetic engineering. This revolution is fueled by a powerful and mysterious 30 nanometer long coil: DNA. The foundations have been set, now it is up to scientists to continue to uncover the secrets of this fascinating molecule and apply it to cure some of the most deadly diseases in the world.

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