This blog post examines the journey of CRISPR gene scissors, originating from bacterial defense systems, to becoming a precise gene editing technology. We explore how this innovation is transforming the medical field.
In recent years, ‘gene scissors’ have become the most significant topic in academia and the biopharmaceutical industry. In 2015, the world-renowned scientific journals Nature and Science selected ‘CRISPR gene scissors’ as the most outstanding achievement of the year. In 2016, National Geographic described it as a “DNA revolution.” Subsequently, in 2020, two researchers jointly won the Nobel Prize in Chemistry for their contributions to developing this technology. In 2023, the first CRISPR-based therapeutic received approval from the U.S. FDA, marking its full-scale expansion into clinical medicine. So, what exactly is ‘CRISPR gene scissors’? What are its principles and innovations that continue to command such attention today?
‘Gene scissors’ refer to a type of ‘genome editing technology’ that can recognize, cut, or edit specific sequences within genes. Among these, ‘CRISPR–Cas9 gene scissors’ consist of the CRISPR sequence and the Cas9 protein, a restriction enzyme capable of cutting and joining DNA. CRISPR stands for ‘Clustered Regularly Interspaced Short Palindromic Repeats’, meaning short palindromic repeat sequences distributed at regular intervals. In other words, specific palindromic sequences (CRISPR) are spaced out and repeated throughout the entire DNA sequence. Here, a palindromic structure refers to a DNA sequence where the base arrangement repeats in reverse, meaning the same sequence appears whether read forward or backward. For example, if one strand’s sequence is GAATTC, the other strand’s sequence is also GAATTC.
How can such seemingly simple ‘CRISPR gene scissors’ precisely locate and cut specific genes among the roughly 30,000 genes in humans? To understand this principle, we must examine bacterial immune responses.
To understand bacterial immune responses, a basic understanding of the structural characteristics of DNA and RNA is first required. DNA is a nucleic acid that stores genetic information in living organisms, forming a double helix structure where two strands are twisted together. Each strand is formed by the polymerization of units called ‘nucleotides,’ and each nucleotide contains one of four types of bases—A (adenine), T (thymine), G (guanine), or C (cytosine). The sequence in which these bases are arranged is called the DNA base sequence. The bases on one strand form hydrogen bonds with the bases on the other strand in a one-to-one complementary pairing: A pairs with T, and C pairs with G. This complementary base pairing maintains the double helix structure of DNA. This property allows the sequence of one strand to predict the sequence of the other strand, and a single strand can find its complementary pairing strand. Specific regions within the DNA sequence that are involved in gene expression are called genes.
RNA is also a nucleic acid, but it consists of a single strand. Its nucleotides contain ‘ribose’ instead of the ‘deoxyribose’ found in DNA. Since RNA also has a base sequence, it can bind to a specific DNA strand if their sequences are complementary. RNA is produced from DNA through a process called ‘transcription’.
Now, let’s examine the bacterial immune response that forms the basis of CRISPR gene scissors, specifically the ‘adaptive immune response’. Immunity refers to the body’s protective reaction against external factors, and adaptive immunity denotes an immune response formed acquired after pathogen invasion, not present innately.
Bacterial adaptive immunity is broadly composed of a ‘memory phase’ and a ‘defense phase’. First, during the memory phase, a protein within the bacterium cuts a portion of the invading virus’s DNA and inserts it between the CRISPR sequences. The space between CRISPR sequences is called a SPACER, and this SPACER stores the viral DNA information.
Once this new nucleotide sequence, containing part of the viral DNA sequence, is formed, an RNA capable of binding complementarily to that sequence is produced; this is called sgRNA. The Cas9 protein binds to this sgRNA.
When the same virus invades again, the second stage, the defense stage, activates. The sgRNA-Cas9 complex utilizes the sgRNA’s ability to bind complementarily to the invading viral DNA to locate the viral DNA. The Cas9 protein then cuts the viral DNA, protecting the bacterium.
Humans drew inspiration from this bacterial immune response to develop technology. They reasoned that attaching a desired human nucleotide sequence to the sgRNA instead of a viral gene would enable selective cleavage of that specific sequence. Indeed, it was confirmed that attaching sequences other than viral ones to the sgRNA enables the same mechanism to function. This established the CRISPR gene-editing technology. In other words, humans gained the ability to remove abnormal genes or insert new ones using CRISPR gene scissors.
The potential applications of CRISPR gene scissors are already being discussed concretely across multiple fields. A prime example is gene therapy, which directly corrects mutated genes. This broadens the range of treatable diseases and enables new approaches to intractable conditions like cancer, AIDS, and genetic disorders. Furthermore, CRISPR’s ability to precisely insert or remove mutations at desired locations enables the development of genetically modified foods with fewer side effects than existing GMO technology. It can also be used for ‘precision gene editing,’ delivering necessary external genes only to specific cells.
This technology also shows diverse potential in environmental and ecological fields. Examples include pest management methods that reduce mosquito populations by controlling their reproductive capacity, or research attempting to restore ancient creatures by introducing mammoth genes into elephant DNA. While these attempts are still in their early stages, they present new potential due to the ability to directly reconstruct genes.
However, several concerns are simultaneously raised: the risk of side effects from immature clinical applications, ethical issues surrounding human embryo manipulation that goes beyond therapeutic purposes to pursue the inheritance of superior traits, and the potential for ecological disruption caused by the emergence of organisms not naturally present in the wild. In reality, what can currently be achieved with CRISPR technology is limited to removing variations or correcting errors in certain genes whose functions are well-understood, and even this is not yet at a stage where accuracy and safety are fully assured.
Nevertheless, CRISPR gene scissors hold immense potential precisely because they can directly alter the genetic information of living organisms. Given that their future direction of application could profoundly impact humanity’s future, a cautious approach is required throughout the entire process of technological development and practical application.
