The CRISPR chronology

How to turn a mistake, yogurt and a little research into a Nobel Prize 

Writer: Priyanka Peres
Editor: Anastasiya Kolesnichenko
Artist: Patrick Marenda

1987, Osaka University: Yoshizumi Ishino’s team accidentally cloned an unusual repetitive sequence of DNA while investigating E. coli bacteria ‒ and it baffled them. When reporting their findings, they included a short paragraph on the last page of their paper mentioning a confusing repeating section of DNA near the target gene in their experiment. They wrote “So far, no sequence homologous to these has been found elsewhere in procaryotes, and the biological significance of these sequences is not known”. 

Many years later, scientists would confirm that Ishino’s team had serendipitously stumbled upon a CRISPR sequence ‒ a small sequence of bacterial DNA that would go on to launch a gene-editing technology revolution. The ensuing story of the discovery of CRISPR is a tale of meticulous observation of the genetic code, but also of dedication, passion and global collaboration. 

Stanford Medicine calls CRISPR “a revolutionary gene-editing tool”. It allows scientists to pinpoint specific genes and edit them. It means that, for the first time, the human race is able to not just read and decode but permanently and accurately tinker with the code of life. The system itself is an immune response found in bacteria to prevent viral infections. It contains three fundamental components: the spacer sequence, the Cas protein and the CRISPR sequence. 

The spacer sequence is a section of a virus genome that is copied and inserted into the bacterial DNA ‒ it helps the CRISPR identify foreign genetic material. Meanwhile, the Cas protein is able to damage or break alien DNA, and the CRISPR sequence codes for a molecule that aligns the components into a single precise killing machine. There are various other components but the discovery of these three were critical in generating an initial understanding of CRISPR systems.

So why was Yoshizumi Ishino so confused by his seemingly simple observation? Repetitive sequences are quite common in DNA. However, the sequences found by Ishino’s team were interesting because they were interspaced by non-repetitive sequences (the spacers) that could not be seen elsewhere in the genome. (Hint: it’s because they didn’t belong to the bacteria E. coli at all). 

2000, University of Alicante, Spain: The first real foray into CRISPR research was made over a decade later and halfway across the world. Francisco Mojica and Ruud Jansen coined the term CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) as a unified term for the newly interesting segments. Along with their contemporaries, Mojica and Jansen made some key observations in the next few years that allowed an early picture of CRISPR systems to form. The first of these was identifying the Cas protein sequence in the DNA. 

About a year later, teams from Spain, France and the Netherlands observed that the spacer sequences interspersed between CRISPRs do not originate from the organism they are studying, but from viruses. Recounts of the time hail this as a truly head-scratching, but fascinating, addition to the growing body of literature on CRISPR. Additionally, Mojica showed that if a bacterium transcribes a spacer sequence from a virus that infects it, the bacterium is immune to that strain of virus. This information generated much speculation about CRISPR’s role as a potential immune system. 

After a basic understanding of the components of the CRISPR system was obtained, there was a gap in research. It was hypothesised that all of these components came together to confer immunity, but the exact mechanism remained unknown for a while. This was when an unlikely hero came to save the day ‒ the yogurt industry. 

2007, North Carolina State University, US: Danisco, a dairy production company, were looking to protect the bacteria manufacturing their yogurt ‒ Streptococcus thermophilus ‒ from viruses. Through their research with Rodolphe Barrangou, Danisco scientists provided evidence for the role of the CRISPR system as a form of adaptive immunity. From that point on, literature and knowledge in this field continued to grow. However, the team that would go on to put the final pieces of the puzzle together didn’t even know each other yet. 

2011, US and Sweden: Jennifer Doudna was working at University of California, Berkeley, and Emmanuelle Charpentier, at Umea University, Sweden. Both women were carefully studying CRISPR systems, and slowly reaching similar conclusions on its potential applications. After bumping into each other at a conference, they would go on to join forces ‒ transforming CRISPR from a bacterial immune tool into a gene editing powerhouse. By 2012, Doudna and Charpentier discovered that this natural adaptive immune system could be hijacked. By customising the spacer sequence used to guide the Cas protein, scientists could target virtually any gene in any species with a kind of genetic ‘scissors’ ‒ which when coupled with additional cellular repair machinery can edit almost any gene. 

Doudna and Charpentier would go on to win the 2020 Nobel Prize in Chemistry for their work on CRISPR. Their discovery has altered biological research forever. In its wake, there was an explosion of new research using CRISPR and it has been widely hailed as the technique that will be the basis for the next century of medical and biological research. As it continues to receive recognition for its potential, it is important to remember that CRISPR was discovered through decades of dedicated work, careful observation and international collaboration. 

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