@@ -31,7 +28,7 @@ Their work was in fact the first report of what would later be named Restriction
The sighting of a second defense system occured more than 40 years later, in the late 1980s, when several teams around the world observed arrays containing short, palindromic DNA repeats clustered together on the bacterial genome :ref{doi=10.1038/nmicrobiol.2017.92}. Yet, the biological function of these repeats was only elucidated in 2007, when a team of researchers demonstrated that these repeats were part of a new anti-phage defense systems :ref{doi=10.1126/science.1138140}, known as [CRISPR-Cas system](https://en.wikipedia.org/wiki/CRISPR).
Following these two major breakthroughs, knowledge of anti-phage systems remained scarce for some years. Yet, in 2011, Makarova and colleagues revealed that anti-phage systems tend to colocalize on the bacterial genome in defense-islands :ref{doi=10.1128/JB.05535-11}. This led to a guilt-by-association hypothesis: if a gene or a set of genes is frequently found in bacterial genomes in close proximity to known defense systems, such as RM or CRISPR-Cas systems, then it might constitute a new defense system. This concept had a large role in the discovery of an impressive diversity of defense systems in a very short amount of time.
Following these two major breakthroughs, knowledge of anti-phage systems remained scarce for some years. Yet, in 2011, it was revealed that anti-phage systems tend to colocalize on the bacterial genome in defense-islands :ref{doi=10.1128/JB.05535-11}. This led to a guilt-by-association hypothesis: if a gene or a set of genes is frequently found in bacterial genomes in close proximity to known defense systems, such as RM or CRISPR-Cas systems, then it might constitute a new defense system. This hypothesis was tested systematically in a landarmark study in 2018 :ref{doi=10.1126/science.aar4120} leading to the discovery of 10 novel anti-phage systems. This started the uncovering of an impressive diversity of defense systems in a very short amount of time :ref{10.1038/s41579-023-00934-x }.
