General Description of the Breakthrough Research
In 2018, Rotem Sorek discovered that the immune system of bacteria was not solely comprised of CRISPR-Cas and restriction-modification systems as previously thought. Using an innovative computational and experimental platform he developed, he discovered many dozens of previously unknown, sophisticated immunity mechanisms employed by bacteria in their combat with their viruses. Sorek’s breakthrough opened many research doors and led to a landslide of discoveries in microbiology, virology and immunology.
A major aspect of Sorek’s discoveries is his demonstration that many important components of the human innate immune system evolved from defense systems that protect bacteria from phage infection. This was completely unexpected because until Sorek’s studies scientists thought that our immune system resulted from evolutionary innovations of multicellular organisms. His studies explained how the human innate immune system evolved, and helped characterize new immune mechanisms in humans and other eukaryotes.
Sorek’s studies also revealed new kinds of small molecules used by both bacteria and eukaryotes for intracellular immune signaling (Cohen Nature 2019; Tal Cell 2021; Ofir Cell 2021), as well as reverse-transcribed non-coding RNAs that mediate defense against phage (Millman, Cell 2020). His studies also showed that some bacteria produce new anti-viral molecules (Bernheim, Nature 2021), which pharmaceutical companies hope will lead to new anti-viral drugs just when humanity needs new disease-fighting resources.
The new research field founded by Sorek now engages many research groups around the world. His studies on the bacterial immune system have been cited thousands of times, and many of the defense systems he discovered are now being studied and characterized by structural biologists, biochemists, bioinformaticians, bacterial geneticists, immunologists and microbial ecologists across disciplines.
Background to the research
Bacteria are frequently infected by viruses called phages. These phages are highly abundant in nature, and are in fact the most abundant viruses on earth. To cope with frequent phage infection, bacteria has developed an immune system that helps them fend off those viruses.
Sorek revolutionized our understanding of how bacteria survive viral infections with his landmark paper titled “Systematic discovery of antiphage defense systems in the microbial pangenome,” (Doron et al, Science 2018). Research from his lab has first pioneered, and then shaped, the notion of the bacterial pan-immune system, which led to the realization that bacteria encode a complex network of anti-phage immune systems. Until his studies, it was believed that the immune system of bacteria was mostly comprised of CRISPR-Cas and restriction-modification systems. But Sorek invented an ingenious computational / experimental method using artificial intelligence that searches for new immune systems among tens of thousands of microbial genomes. This has enabled Sorek and his team to study >50 completely new and widespread multi-gene immune systems. Sorek is considered the founder and the world leader of this research field.
Many of the bacterial immune systems discovered by Sorek turned out to be the ancient source for the evolution of human and plant innate immunity. Among his discoveries, he showed that the cGAS-STING antiviral pathway, originally discovered in animals, is also widespread in bacteria and protects them against phage infection (Cohen et al, Nature 2019). In addition, he found that genes with Toll-interleukin receptor (TIR) domains are involved in bacterial defense against phages, providing evidence for a common, ancient ancestry of innate immunity components shared between animals, plants, and bacteria (Doron et al, Science 2018; Ofir et al, Nature 2021). Just recently, Sorek found that an important human inflammatory process called Pyroptosis also originated from bacteria (Johnson, Wein et al, Science 2022). Sorek’s discoveries have explained much about the evolution of the human cell-autonomous innate immune system, including solving new mechanisms in the animal and plant immune systems (e.g., Ofir, Nature 2021).
In another groundbreaking discovery, Sorek found that some bacterial immune systems can produce a variety of small molecule inhibitors of viral replication (Bernheim, Nature 2021). His data revealed a goldmine of anti-viral molecules that are generated by bacteria and could be harvested and adopted for clinical use.
Sorek’s pursuits are truly astonishing. Currently, he is deciphering the molecular mechanisms of many of those numerous new immune systems he found. In the past, the discovery and characterization of novel immune systems proved extremely useful biomedically because they entail specific molecular recognition and targeting characteristics (examples include restriction enzymes, CRISPR-Cas, RNAi, etc.). We can anticipate that Sorek’s discoveries of new prokaryotic immune systems will lead to more beneficial molecular tools in biomedicine.
Another profound contribution Sorek has made is discovering that viruses can use small-molecule based communication to coordinate their infection dynamics (Erez et al., Nature 2017). Effectively, he showed that viruses can make group decisions – insight that has launched the new scientific field of “sociovirology.” These discoveries represent a paradigm shift in virology and may potentially extend into viruses that infect more complex organisms such as humans.
Sorek is one of the most famous, prominent, and highly accomplished microbiologists in the world, well recognized for his work on the interactions between bacteria and the viruses that infect them. His discoveries on the immune system of bacteria have opened completely new fields in microbiology and have made paradigm shifts in virology. Prof. Sorek’s scientific excellence is demonstrated both by his extraordinary creativity and innovation and by his high level of productivity.
Apart from his impressive achievements in basic research, Rotem Sorek is also a very prolific and innovative inventor with 40 patents and patent applications. Nine of these patents have been licensed to biotech companies. Technologies invented in the Sorek lab were the basis for establishing three start-up companies.
Dr. Sorek has been honoured with many prestigious prizes including the Clore Prize (2008), the EMBO-YIP Award (2010), the Rubinowitz-Grossman Prize for outstanding scientists in microbiology (2012), the Teva Founders Award for young researchers (2013), the FEBS Anniversary Prize (2014), the Scientific Council Prize in Life Sciences (2016), the Beutler Award (2019), the Deloro Prize (2021), the Rappaport Prize (2021), and the Landau Award (2022).
In recognition of his substantial contributions, Sorek was appointed as a member of the Young Israel Academy of Sciences and Humanities (2012) and was elected to the European Academy of Microbiology (2015), the American Academy of Microbiology (2018), EMBO (2018), and the German National Academy of Sciences Leopoldina (2022).
Doron S, Melamed S, Ofir G, Leavitt A, Lopatina A, Keren M, Amitai G, Sorek R. Systematic discovery of new anti-phage defense systems in the microbial pan-genome. Science, 359, pii: eaar4120 (2018).
Cohen D, Melamed S, Millman A, Shulman G, Oppenheimer-Shaanan Y, Kacen A, Doron S, Amitai G, Sorek R. Cyclic GMP-AMP signalling protects bacteria against viral infection. Nature, 574:691-695 (2019).
Millman A, Bernheim A, Stokar-Avihail A, Fedorenko T, Voichek M, Leavitt A, Oppenheimer-Shaanan O, Sorek R. Bacterial retrons function in anti-phage defense. Cell, 183(6):1551-1561 (2020).
Bernheim A, Millman A, Ofir G, Meitav G, Avraham C, Shomar H, Rosenberg MM, Tal N, Melamed S, Amitai G, Sorek R. Prokaryotic viperins produce diverse antiviral molecules. Nature, 589(7840):120-124 (2021).
Erez Z, Steinberger-Levy I, Shamir M, Doron S, Stokar-Avihail A, Peleg Y, Melamed S, Leavitt A, Savidor A, Albeck S, Amitai G, Sorek R. Communication between viruses guides lysis-lysogeny decisions. Nature, 541(7638):488-493 (2017).