What's CRISPR, Anyway?

How it came together

There was a meeting of minds in Puerto Rico in 2011. At a conference for Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) systems and RNA Biology held in San Juan, Emanuelle Charpentier, a young microbiology researcher at the Umeå University in Sweden, presented her findings on a new RNA-protein complex that played a role in the function of a bacterial immune system. The presentation was a wake-up call for Jennifer Doudna, who studied the specific biochemical relationships related to RNA and believed that this mechanism could have wider implications.

At the time, the CRISPR molecule was considered a niche field of study rather than the widely used gene editing tool that it has become now. It concerned a specific bacterial defense response against viruses, which involved an enzyme (Cas9) that performed precise incisions in the DNA as well as an attached RNA molecule which led it to the site of interest. In other words, the system was made up of ultra-precise molecular scissors and a guide. But the problem was that the guide could not be replicated by scientists; it was impossible to modify. 

A year after the conference, the final piece to the puzzle of precise genome editing that spanned decades was finally put in place; working together, Doudna and Charpentier discovered the crucial customizable guide that would allow the natural process to be co-opted in lab conditions outside of the bacterial cells that fostered the conditions that allowed the process to happen naturally. 

The short time of eight years spanning CRISPR’s discovery and the jointly awarded Nobel prize in Chemistry is just a small indicator of its seismic impact. But as is usual regarding scientific discoveries, it is difficult to understand what the repercussions of even the biggest breakthroughs entail for the future of everyday life. So where should we start?

What is genetic engineering, really?

Anyone who’s taken a beginner Biology course knows that the cell is the fundamental building block of life. Our bodies are made up of tens of trillions of cells, each with a different set of internal machinery and function. Deoxyribonucleic acid, commonly known as DNA, is the molecular blueprint that exists within each cell and determines its unique functions. This is made possible by the double-helix structure of the DNA itself, which essentially comprises two long strings of molecular code that are copied, sent out into the cytoplasm and used to create all the important molecules that cells need to survive and carry out their function. The important thing to understand here is that the code of the DNA—save for mutations, viral/bacterial invasions and a few other exceptions—stays the same and is the essential determinant of its host cell’s identity. A change in even a single unit of code within the DNA could result in the complete breakdown of the cell or in an improvement of a given function. But the latter, logically enough, happens much more rarely than the former—most mutations are either neutral or detrimental. While natural selection provides a process by which the many bad mutations are filtered out while the few good ones carry themselves to the next generation, ‘bad’ and ‘good’ are relative terms. A watermelon that has an increased seed density has more chances of spreading those seeds and propagate its DNA across generations, but yields less nutritious value for us humans. 

Genetic engineering, then, is the purposeful manipulation of organisms’ genomes to fit our purposes. Funnily enough, we started doing it thousands of years before we had any idea about DNA; selective breeding of animals and plants to create friendly and obedient dogs out of wolves and sweet and near-seedless watermelons is a testament to that. But this method is not a very effective way to edit genomes. It’s limited to mutations that occur naturally in plants, often taking multiple breeding generations to yield reliable results, and is not precise at all; in naturally occurring mutations, stretches of DNA might be altered along with the gene of interest. 

What does CRISPR add?

Ever since the discovery of DNA in the 20th century, scientists had been coming up with effective ways to induce targeted genome manipulations. Initially, these efforts included bombarding plants with radiation in the hopes that a useful mutation would pop up. In the 70s and 80s, more sophisticated methods developed with the discovery of specialized restriction enzymes that recognized and cut specific sections of DNA, as well co-opting bacteria such as agrobacterium to use as delivery mechanisms for genes of interest into the cell. 

But still, all of these mechanisms presented significant limitations: while high levels of radiation fast-tracked the process of mutation, researchers had no control over the actual changes occurring over the genetic code; restriction enzymes were fixed, and could only recognize certain sequences of a specific length; the agrobacterium delivery system worked only in plants and inserted genes randomly in their genomes, thus potentially nullifying their function. 

Instead, easy manipulation of the CRISPR RNA-protein complex in laboratory settings means that the system is programmable and precise. It can perform different types of ‘incisions’ on any part of the genome depending on the manipulation. The ease and efficiency of this mechanism means that genetic engineering becomes not only incredibly quicker, but also much cheaper. Its performance-enhancing capabilities enable a higher rate of experimentation and therefore discovery.

What has CRISPR achieved so far?

CRISPR’s versatility opens the door to an entirely new, more hands-on generation of genetic engineering across fields. In terms of agriculture, it provides an important avenue into more efficient and precise genetic altering of plants. As mentioned before, humans have for centuries employed a rudimentary form of genetic manipulation (selective breeding) that is way too imprecise and slow. The same problem exists in different degrees with more modern methods of genetic engineering such as the introduction of new DNA via bacteria. 

Even though CRISPR technologies are not fully developed yet and their delivery faces difficulties, they are crucial to a more precise and effective creation of GMOs. It means that plants are more resilient to adverse conditions such as extreme temperatures and pesticides, in turn aiding crop outputs in an age of climate change and rapid populational growth.

CRISPR-Cas9 also offers a more accurate method to simulate how genes are passed down and mutate across generations. From mammals to insects, the tool has been used to swap out sections of DNA with ones of interest in order to help scientists better understand how these genes behave; whether they have a tendency to replicate and what molecules, if any, they provide the blueprints for.

With gene therapy, CRISPR adds an entirely new and powerful treatment method that enhances our clinical toolset. In 2014, the first instance of this was trialled in the UK to treat a patient with sickle cell anaemia. Commercially known as Casgevy, it involved the extraction of the problematic mass-producing cells responsible for the production of defective red blood cells, as well as their subsequent DNA modification before reinserting them back into patients’ bone marrow. Late in 2023, both the UK and US approved the commercial use of such drugs. A slew of other such gene therapy treatments follow; promising treatments for brain and ovarian cancer, diabetes and even AIDS. 

The emergence of CRISPR gene-editing in a clinical setting, however, poses serious ethical concerns. After gaining governmental permission, for example, researchers in the UK successfully modified human embryos in 2016. Even though they were later discarded, the scientific feat signifies that it is now possible to pick and choose our babies’ genomes. But should we be able to change the genetic makeup of an embryo? If so, would it only be to prevent life-threatening congenital diseases like Hypoplastic Left Heart Syndrome or less serious medical conditions such as dwarfism as well? Disability activists such as Rebecca Cokley, who views her achondroplasia less as a disease than as a  part of her identity, argue that CRISPR is an existential menace to people like her. Purely cosmetic gene edits, such as those that would increase height or intelligence, are even more controversial; the concept of designer babies, previously a fit of science fiction fancy, looms as a frightening prospect that could entrench social inequalities by embedding them into our very genomes. 

Conclusion

Despite technical limitations and ethical considerations, it’s hard to understate the revolutionary nature of the CRISPR system. In just over a decade, its use has proliferated to the majority of fields within the life sciences, yielding important clinical advances to tackle congenital diseases and understand viral mechanisms that target humans in order to accelerate the vaccine-making process. With all this, it’s important to note that the Cas9-system is only the first of many generations to come. Already, discovery of protein complexes such as Cas12 and present more precise and less error-prone mechanisms.  In any case, one thing is clear: the discovery of CRISPR marks the beginning of a new age in genetic engineering.