Rotem Sorek

During his graduate studies in human genomics at Tel Aviv University, Rotem Sorek was able to witness the completion of the Human Genome Project, which was an experience that gave him appreciation for the potential of genomics to explain many of life’s mysteries. However, as he neared the end of his Ph.D. studies, Sorek made the decision to switch to studying microbial genomics, based on his perception that discovering fundamental insights about life could be best achieved by taking a broad look at microbial genomics. “I started thinking that if one was to discover something fundamental about life, then looking at just one organism has a lower chance for discoveries,” Sorek says. “At the time, and still now, it became apparent that microbes hold an enormous amount of functions that are unknown. If you look at one genome of bacteria, about half of the genes are of unknown functions. In the millions of bacterial genomes that have already been sequenced, there are many different functions to discover.” 

So instead of taking a deeper look at human genomics, Sorek decided to switch tracks, in order to take a broader look at microbial genomics, in the hopes that studying a wide swath of microbial genomes in parallel could yield fundamental insights about life. Sorek decided to do his postdoctoral research at Lawrence Berkeley National Lab, in order to gain training in microbial genomics. During his postdoctoral research, he became acquainted with CRISPR, which at the time, was one of two known bacterial defense systems that defended against viral infections. “What puzzled me about CRISPR is that this was a system that was very profound, and yet it was discovered 90 years after the discovery of phages,” Sorek says. “The reason that CRISPR was discovered so late is because it is not very active in the model organisms that we have in the lab. That turned my attention to asking, is it possible that there are more immune systems out there, that we are not aware of?”

After taking a faculty position at the Weizmann Institute of Science in Rehovot, Israel, Sorek turned his attention to studying the genomics of a broad range of microbes, with a goal of identifying additional bacterial defense systems, similar to CRISPR. In order to find more bacterial defense systems, Sorek and his colleagues devised a large-scale computational screen for searching the genomes of tens of thousands of bacteria, as well as an experimental system that could validate any candidate defense systems that they found. Their computational screen was based on the observation that CRISPR was often found near other immune systems, such as restriction enzymes. 

Using this screen, Sorek and his team, who called themselves the “Defense Council,” were able to identify a number of candidate genes for immune defense systems, which were then experimentally validated. “Predicting defense systems has a limited merit,” Sorek says. “In order to validate these predicted systems, we had to develop an experimental method to test them.

In a landmark paper, published in 2018, in the journal Science, Sorek and collaborators described nine new families of antiphage defense systems and one family of antiplasmid systems, which were capable of defending against infection. These results had the effect of opening up a new field in microbiology, one that illuminated the large number of mechanisms that are used to guard against viral infections, and has led to many profound insights about how the human immune system works. 

In follow-up studies, Sorek and his collaborators were able to solve a number of long-standing mysteries in the field. This includes the discovery that the cGAS-STING pathway, which is an antiviral pathway found in humans, had evolutionary origins in a bacterial anti-phage defense system. As Sorek notes, although components of the human immune system, such as antibodies, only developed later, there are aspects of the human immune system, such as the cell autonomous immune system, that are conserved from bacteria to humans. “That was surprising because, until then, the human immune system was thought to be a later innovation of multicellular organisms,” Sorek says. 

They were also able to show that retrons, which are chimeric nucleic acid molecules in which RNA and DNA molecules are covalently bound together, play a role in protecting bacteria against infection, thus solving a decades-old mystery about the nature of these molecules. Sorek and his collaborators were also able to identify a number of small molecule viral inhibitors, which are currently being studied for their use as antiviral medications. 

Moving forward, Sorek plans to continue studying the defense systems of bacteria, with the hope that it can yield additional insights about how bacteria can defend against viral infection, and how these mechanisms apply to the human immune system. “We now know there are more than 200 new types of defense systems, but only for a minority of them do we know the function,” Sorek says. “I hope to find more parallels, both in terms of shared evolution and in terms of immunological concepts, that connect between bacterial immunity, human immunity and plant immunity.”