2025 Gruber Genetics Prize

After completing a Ph.D. in human genomics at Tel Aviv University, Rotem Sorek made the decision to switch to studying microbial genomics, due to the 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. With the millions of sequenced bacterial genomes out there, there are many different functions to discover.” 

Sorek decided to do his postdoctoral research at Lawrence Berkeley National Lab, switching over to studying 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. 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. “We synthesized the candidate immune system, then installed them in the genomes of E. coli or Bacillus subtilis, and then infected these bacteria with many different phages, to see if there is defense,” Sorek says. 

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, all of which were identified using their approach. 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 a number of profound discoveries about the human immune system. “By now, we know from our work, and the work of others, that bacteria have more than 200 different kinds of defense systems,” Sorek says. “That knowledge started from our screens.”

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. “We very surprisingly discovered that some of these immune systems we found in bacteria are also shared between bacteria and our own immune systems,” Sorek says. “That was surprising because, until then, the human immune system was thought to be a later innovation of multicellular organisms.”

They were also able to show that retrons, which are chimeric nucleic acid molecules in which RNA and DNA molecules are covalently bound, 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.